TWI527813B - Substituted n-(1h-indazol-4-yl)imidazo(1,2-a)pyridine-3-carboxamide compounds as type iii receptor tyrosine kinase inhibitors - Google Patents

Description

Substituted N-(1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a type III receptor tyrosine kinase inhibitor

The present invention relates to novel compounds, pharmaceutical compositions comprising such compounds, methods of preparing such compounds, and the use of such compounds in therapy. More specifically, the present invention relates to certain substituted N-(1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide compounds, such as PDGFR and/ Or an inhibitor of cFMS and/or cKIT type III receptor tyrosine kinase for the treatment of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, pain and burns.

PDGFR is expressed on early stem cells, mast cells, bone marrow cells, mesenchymal cells, and smooth muscle cells. PDGFR-β has been implicated in myeloid leukemia. Recently, activating mutations in the PDGFR-α kinase domain have been shown in gastrointestinal stromal tumors (GIST) (Wong et al., 2007, Histopathology 51(6): 758-762).

PDGFR has been shown to be an effective mitogen for myofibroblast formation (a hallmark of fibrotic conditions and involved in the progression of fibrosis) (Bonner, J. et al., 1998, American Journal Physiology 274 (1Pt1): L72-L80) .

Furthermore, it has been demonstrated in various experimental models that blocking PDGF signaling will reduce the occurrence of fibrosis (Yoshiji et al, 2006, Int. J. Mol. Med. 17: 899-904). For example, Imatinib, a known PDGF signaling inhibitor, has exhibited anti-fibrotic activity in several fibrotic animal models (Akhmetshina, A. et al., 2009, Arthritis Rheumatism 60 (1) : 219-224; Vuorinen, K. et al., 2007, Experimental Lung Research 33(7): 357-373; Aono, Y. et al., 2005, American Journal Respiratory Critical Care Medicine 171(11): 1279-1285) . Several cases of patients with fibrotic disease benefit from imatinib therapy (Kay, J. et al., 2008, Arthritis Rheumatism 58(8): 2543-2548; Distler J. et al., 2008, Arthritis Rheumatism 58 ( 8): 2538-2542; Hirose, Y. et al., 2002 International Journal Hematology 76(4): 349-353). Recently, imatinib completed a randomized, placebo-controlled phase II study in patients with idiopathic pulmonary fibrosis (IPF).

The macrophage colony stimulating factor-1 receptor (CSF-1R; a tyrosine receptor kinase, also known as cFMS) is a receptor for colony stimulating factor-1 (CSF-1), also known as M-CSF. CSF-1 is an important growth factor for bone precursor cells, monocytes, macrophages, and macrophage lineage cells such as osteoclasts and dendritic cells. Binding of CSF-1 to the extracellular domain of cFMS will induce cFMS dimerization and trans-autophosphorylation of the intracellular cFMS kinase domain. Once phosphorylation occurs, cFMS acts as a docking site for several cytoplasmic signaling molecules, and activation of these molecules will result in gene expression and proliferation from scratch. The robust performance of cFMS is limited to monocytes, tissue macrophages, and osteoclasts, so cFMS inhibitors can be used to treat osteoclasts, dendritic cells, and macrophages that act as pathogens, such as autoimmune/inflammatory. Disease, cancer and bone related diseases.

Bones are an ever-changing organization that continues to undergo a reconstruction process that works to maintain bone strength and health. This reconstruction process requires two phases: the osteolysis phase and the osteogenic phase. During osteolysis, osteoclasts invade the bone and erode bone by releasing acids and enzymes that dissolve collagen and minerals. This process creates small holes in the bone. During bone formation, osteoblasts deposit new collagen and minerals into the cavity. When bone dissolution and bone formation are in equilibrium, there is no net change in bone quality. However, in certain disease states, osteolysis is more active than bone formation, resulting in a net loss of bone.

One particularly serious cause of localized excessive osteolysis is the metastasis of cancer to the bone. Cancer cells typically secrete factors that promote osteoclast development and activity, such as M-CSF. When these cancers themselves settle in the bone, they promote a wide range of osteolytic lesions and can cause, for example, fractures and spinal cord compression. Such tumor-associated osteolysis occurs simultaneously with many types of malignant diseases, including hematological malignancies (such as myeloma and lymphoma) and solid tumors (such as breast, prostate, lung, kidney, and thyroid tumors). Therefore, there is still a need for a therapy that reduces or delays the complications caused by the spread of cancer to the bone.

When excessive bone dissolution occurs in a large area of the bone, it falls into the category of osteoporosis generally described. Common types of osteoporosis include age-related, postmenopausal, treatment-induced bone loss (eg, caused by glucocorticosteroids, aromatase inhibitors, or anti-androgen therapy), diabetes-related, and disuse osteoporosis disease. In the United States alone, millions of individuals suffer from the disease and the resulting pain, deformity and degenerative fractures.

Osteoclasts are multinucleated cells derived from monocyte precursors and functioning under a variety of cytokines and growth factors. The differentiation of monocyte precursors into osteoclasts requires a complex process of M-CSF and RANKL, the receptor activation factor of NF-κB ligands. Inhibition of osteoclast development and function is an ideal method for the treatment of excessive osteolysis. However, substances currently available for this purpose have limited utility and often cause significant side effects. Therefore, there is a continuing need for effective and practical treatments for excessive osteolytic conditions.

Macrophages associated with osteoclasts play an important role in inflammatory diseases, cancer and bone disorders. For example, macrophages associated with osteoclasts are a major component of host cell responses to cancer and can contribute to tumor growth. In particular, both macrophages and tumor cells secrete M-CSF, which is a key cytokine for monocyte precursors to develop into osteoclasts. Macrophages as well as monocytes and some tumor cells also express M-CSF receptors.

Solid tumors contain a variety of cell types, including macrophages. These tumor-associated macrophages (TAMs) play a role in promoting tumor progression and metastasis (Pollard, JW, Nat. Rev. Cancer, 2004, 4:71; Lewis, CE and Pollard, JW, Cancer Res., 2006, 66: 605). After recruitment to the tumor environment, macrophages immediately release the factors involved in tumor cell growth and migration. Monocyte/macrophage development and proliferation depend on the signal transduction pathway of CSF-1R and its ligand CSF-1. A recent depletion study in cancer models shows the role of M-CSF in promoting tumor growth and progression to metastasis (Chitu, V. and Stanley, ER, Curr. Opin. Immunol., 2006, 18). : 39-48; Pollard, JW, Nature Rev. Cancer, 2004, 80: 59-65; Paulus, P. et al., Cancer Res. 2006, 66: 4349-4356). Therefore, inhibition of this pathway can reduce the TAM content, resulting in multiple effects for tumor types with a very large number of macrophages.

Macrophages are also a major source of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in destructive joint spasm of rheumatoid arthritis. TNF and IL-1 activate cell matrix manifestations of hematopoietic factors including CSF-1. CSF-1, in turn, recruits monocytes and promotes macrophage survival, functional activation, and, in some cases, proliferation. Thus, TNF and CSF-1 interact in a perpetual loop that causes inflammation and joint destruction. The number of macrophages is also increased in atherosclerotic plaques (Arch. Pathol. Lab. Med. 1985, 109: 445-449), and it is believed that macrophages in atherosclerotic plaques cause disease progression.

The inflammatory mechanism of stagnation also plays an important role in hyperalgesia caused by nerve damage. Nerve damage can stimulate macrophage infiltration and increase the number of activated T cells (Abbadie, C., 2005, Trends Immunol. 26(1): 529-534). In these cases, as with the initial injury itself, nerve inflammation and immune response cause pain to occur and persist. In an animal model in which macrophages are depleted after ligation of the sciatic nerve (Liu et al, Pain, 2000, 86: 25-32), the neuropathology of the loop monocytes/macrophages in local nerve injury is confirmed. The role played by hyperalgesia and the emergence of Wallerian degeneration. In this study, treatment of nerve-damaged rats with liposomally encapsulated Cl ₂ MDP (dichloromethylene diphosphonic acid) will alleviate thermal hyperalgesia and reduce degeneration of myelin and demyelinated axons. It is reported that the liposome encapsulated Cl ₂ MDP can effectively reduce the number of macrophages in the nerve segment. Furthermore, in many cases, neuropathic pain is associated with neuroinflammation (neuritis) that occurs in the absence of nerve damage. According to an animal model of neuritis (Tal M., Curr. Rev. Pain 1999, 3(6): 440-446), it has been proposed that some cytokines play a role in nociception and hyperalgesia by causing peripheral sensitization. No trauma or classic tissue inflammation was found during this process. Thus, depletion of macrophages by administration of cFMS inhibitors has clinical potential for treating or preventing neuropathic pain that is caused by nerve damage and in the absence of nerve damage.

Several types of cFMS small molecule inhibitors are known to be suitable for the treatment of cancer, autoimmune and inflammatory diseases (Huang, H. et al., J. Med. Chem, 2009, 52, 1081-1099; Scott, DA, etc. Human, Bioorg. & Med. Chem. Lett., 2009, 19, 697-700).

The C-KIT receptor system, also known as CD117, is expressed on the surface of various cell types including hematopoietic stem cells. This cytokine receptor is associated with certain forms of gastric cancer (Novak, C. et al., 2010 Mini Rev. Med. Chem. 10(7): 624-634). Both imatinib and sunitinib are cKIT inhibitors and are generally effective in treating patients with GIST. However, the patient will eventually develop resistance to both agents and alternative options are still limited.

There is evidence that cKIT and mast cells play a detrimental role in fibrotic conditions. For example, in bronchiolitis obliterans, mast cells are concentrated in the small airway epithelial membrane (Fuehrer, N. et al., 2009, Archives Pathology Laboratory Medicine 133(9): 1420-1425). In addition, there is evidence to suggest that cKIT-positive cells are involved in the pathogenesis of obstruction of the ureteropelvic junction (Ozel, S. et al., 2009, Journal Pediatric Urology, August 27).

Pulmonary arterial hypertension (PAH) involves elevated blood pressure in the pulmonary arteries, and there is evidence that abnormalities in the function of endothelial progenitor cells overexpressing cKIT cause PAH conditions (Toshner, M. et al., 2009, American Journal Critical Care Medicine 180 (8) ): 780-787).

It has now been found that certain substituted N-(1H-oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide compounds are of type III such as PDGFR, cFMS and/or cKIT. An inhibitor of the receptor tyrosine kinase and useful for treating conditions and diseases that are sensitive to inhibition of such kinases.

Accordingly, one embodiment of the invention provides a compound of formula I :

Or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} as defined herein.

In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I and a carrier, diluent or excipient.

In another aspect of the invention, there is provided a method of inhibiting a type III receptor tyrosine kinase, such as PGDFR, cFMS and/or cKIT, in a mammal, the method comprising administering to the mammal in need thereof a therapeutically effective amount A compound of formula I.

In another aspect of the invention, a disease or condition for treating a disease or condition selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, pain, and burns in a mammal is provided. A method of administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a mammal in need thereof.

In another aspect of the invention, a method for treating a disease or condition selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, and pain in a mammal, The method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, there is provided the use of a compound of Formula I, the compound is of Formula I for use in treating a mammal for the selected fibrosis, bone-related diseases, cancer, immune disorders, inflammatory diseases autologous, A medicament for a disease or condition of cardiovascular disease, pain and burns, the treatment comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, there is provided the use of a compound of Formula I, the compound is of Formula I for use in treating a mammal for the selected fibrosis, bone-related diseases, cancer, immune disorders, inflammatory diseases autologous, A medicament for a disease or condition of cardiovascular disease and pain, the treatment comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, there is provided the use of a compound of Formula I, the compounds of formula I are for the treatment of a mammal selected from fibrosis, bone-related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular A disease or condition of disease and pain.

In another aspect of the invention, there is provided a compound of formula I for use in the treatment of a mammal selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, pain and burns. a disease or condition.

In another aspect of the invention, there is provided a compound of formula I for use in the treatment of a disease selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases and pain in mammals. Or illness.

Another aspect provides an intermediate for the preparation of a compound of formula I. In one embodiment, certain compounds of formula I are useful as intermediates in the preparation of other compounds of formula I.

Another aspect includes processes for the preparation of the compounds described herein, methods of isolation, and methods of purifying the compounds described herein.

According to one embodiment, the invention provides a compound of formula I :

Or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ -, hetAr ³ CH ₂ -, (3-6C cycloalkyl)-CH ₂ -, hetCyc ¹ CH ₂ -, Ar ¹ (CH ₂ ) _n - or (N-1-3C alkyl)pyridinyl-CH ₂ -; hetAr ¹ is a 6-membered heteroaryl group having 1-2 ring N atoms, Substituting one or more substituents independently selected from (1-6C)alkyl, (1-4C)alkoxy, halogen, CF ₃ or (3-6C)cycloalkyl; m is 0,1 or ^2; hetAr 2 is a 2-3 having 5 ring heteroatoms independently selected from N and S atoms of ring membered heteroaryl, wherein such at least one of the heteroatoms is N, wherein the ring optionally substituted with one or more Hetero ³ is a bicyclic 5,6-fused heteroaryl ring having two ring nitrogen atoms; hetCyc ¹ has 1-2 independently selected from N and a 6-membered saturated heterocyclic ring of a hetero atom of O, optionally substituted by -C(=O)(1-6C alkyl) or -C(=O)O(1-6C alkyl); Ar ¹ is benzene And optionally substituted by one or more substituents independently selected from the group consisting of halogen, (1-6C)alkyl, CN, CF ₃ , OH, (1-6C) alkoxy, -C ( =O)OH, -C(=O)O(1-6C alkyl), -C(=O)NR ^a R ^b Or benzyloxy; R ^a and R ^{b are} independently H or (1-6C)alkyl; n is 0, 1 or 2; R ² is H, F, Cl or CH ₃ ; R ³ is H, F Or Cl; R ⁴ is H, CN, F, Cl, Br, -OMe, -OCF ₃ , -CF ₃ , -CH(OH)CH ₂ OH or -C(=O)NH ₂ ; R ⁵ is selected from :H, halogen, CN, OH, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ (1-4C alkyl)-, hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy , (1-3C alkoxy) (1-4C) alkoxy, hydroxy (1-6C) alkoxy, dihydroxy (2-6C) alkoxy, (1-6C) alkoxy, [hydroxyl (2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl, [di( 1-4C alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [Bis(1-3C alkyl)amino](1-4C)alkoxy, N-(1-3C alkyl)pyridone, hetAr ⁶ , hetCyc ⁶ C(=O)-, (hetCyc ⁷ )- O-, hetCyc ⁸ (1-4C) alkoxy, difluoroamino (1-4C) alkoxy, [(1-4C alkoxy)carbonylguanamine] difluoro(1-4C) alkoxy , (1-4C alkyl) C (= O) NH ( 2-4C) alkylthio -, (1-4C alkyl) OC (= O) -, R & lt ^{D C} and the NC R & lt (O =) -; hetAr ⁴ having 1-3 heteroatoms independently selected from N, O Five ring heteroatoms of S heteroaryl ring, wherein the ring optionally substituted with one or more groups independently selected from (1-6C) alkyl, and [di (1-3C alkyl) amino] CH ₂ - the substituents Substituent; hetAr ⁵ is a 6-membered heteroaryl ring having 1-2 ring N atoms, optionally substituted with one or more substituents independently selected from (1-6C)alkyl; hetAr ⁶ is 3 a 9-membered partially unsaturated bicyclic heterocyclic ring of a ring N atom, which is optionally substituted with one or more substituents independently selected from (1-6C)alkyl; hetCyc ² has 1-2 selected from N and O a 5-7 membered saturated or partially unsaturated heterocyclic ring of a heteroatom of a ring wherein the ring is optionally selected from one or more independently selected from the group consisting of (1-6C)alkyl, hydroxy(1-6C)alkyl, OH, and pendant oxygen. Substituent substitution, the limitation is that the pendant oxy group is on a carbon atom; hetCyc ³ is a 4-6 membered heterocyclic ring having 1-2 ring N atoms, which is optionally independently selected from one or more ( 1-6C) substituted with a substituent of an alkyl group, a (1-6C) alkoxy group and a halogen; hetCyc ⁴ is a 4-7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S, Wherein one of the ring nitrogen atoms is oxidized to N(O) as appropriate, and wherein the S ring atom is optionally oxygen To SO or SO _2, wherein hetCyc ⁴ optionally substituted with one or more groups independently selected from halogen, OH, (1-6C) alkyl, (1-4C alkoxy) (l-6C) alkyl, (1- 4C) Substituent substitution of alkyl-OC(=O)- and (1-6C)alkoxy; hetCyc ⁵ is a spiroheterocycle having 2 ring heteroatoms independently selected from N and O, wherein hetCyc ⁵ The case is substituted with a group selected from a (1-6C) alkyl group; hetCyc ⁶ is a 6-membered heterocyclic ring having 1-2 ring N atoms, which is optionally independently selected from (1-6C) alkane by one or more the group substituents; hetCyc ⁷ is a 4-6 membered heterocyclic ring having one or two ring N atoms, which is optionally substituted with one or more groups independently selected from (1-6C) alkyl and the OH substituents; hetCyc ⁸ is a bridged 8-membered heterocyclic ring having two ring atoms selected from N and O, wherein at least one of the hetero atoms is N, wherein the ring is optionally substituted by (1-6C)alkyl; R ^c is H or (1-4C)alkyl; R ^d is (1-4C)alkyl, hetCyc ¹⁰ -,amino(1-4C)alkyl or [di(1-4Calkyl)amino](1- 4C)alkyl; hetCyc ¹⁰ is a 5-membered heterocyclic ring having a ring of N atoms, optionally substituted with one or more substituents independently selected from (1-6C)alkyl; and R ⁶ is H or Cl.

The compounds of formula I are inhibitors of type III receptor tyrosine kinases such as PDGFR, cFMS and cKIT, and are useful in the treatment of mammals in need thereof, selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammation. A disease or condition of sexually transmitted diseases, cardiovascular diseases, and pain.

In one embodiment, R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ -.

In one embodiment, R ¹ is hetAr ¹ (CH ₂ ) _m —, wherein hetAr ¹ is a 6-membered heteroaryl having 1-2 ring N atoms, optionally selected from one or more -6C) Substituent substitution of an alkyl group, a (1-4C) alkoxy group, a halogen, a CF ₃ or a (3-6C) cycloalkyl group. In one embodiment, hetAr ¹ is pyridyl or pyrimidinyl. In one embodiment, hetAr ¹ is pyridyl.

Examples of the (1-6C) alkyl substituent of hetAr ¹ include a (1-4C) alkyl substituent such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butylene. And a third butyl group.

Specific examples of the (1-4C) alkoxy substituent of hetAr ¹ include a methoxy group and an ethoxy group.

A specific example of a halogen substituent of hetAr ¹ is fluorine.

Specific examples of the (3-6C) cycloalkyl substituent of hetAr ¹ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

In certain embodiments, R ¹ is hetAr ¹ (CH ₂ ) _m —, wherein hetAr ¹ is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms, which is optionally independently selected from one or more methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, fluoro, CF _3, cyclopropyl, cyclobutyl or cyclopentyl Substituent substitution. In certain embodiments, hetAr ^{1 is} optionally substituted with one or both of the substituents. In certain embodiments, hetAr ¹ is a pyridyl group optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl, and second. Butyl, tert-butyl, methoxy, ethoxy, fluoro, CF ₃ , cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, m is zero. In certain embodiments, m is one. In certain embodiments, m is two.

When represented by hetAr ¹ (CH ₂ ) _m -, the specific value of R ¹ includes the following structure:

In one embodiment, R ¹ is hetAr ² CH ₂ -, wherein hetAr ² is a 5-membered heteroaryl ring having 2-3 ring heteroatoms independently selected from N and S, wherein at least one of the heteroatoms Is N, wherein the ring is optionally substituted with one or more substituents independently selected from (1-6C)alkyl. In one embodiment, hetAr ² is a 5-membered heteroaryl ring having 2 ring heteroatoms independently selected from N and S, wherein at least one of the heteroatoms is N, wherein the ring is one or more Substituents independently selected from (1-6C) alkyl groups. Specific examples of the hetAr ² ring include a thiazolyl group, a pyrazolyl group, and an imidazolyl group. Examples of the (1-6C) alkyl substituent of hetAr ² include a (1-4C) alkyl group such as a methyl group, an ethyl group, a propyl group and an isopropyl group. In one embodiment, hetAr ^{2 is} optionally substituted with one or both of the substituents.

When represented by hetAr ² CH ₂ , specific examples of R ¹ include the following structures:

In one embodiment, R ¹ is hetAr ³ CH ₂ -, wherein hetAr ³ is a bicyclic 5,6-fused heteroaryl ring having two ring nitrogen atoms. A specific example of hetAr ³ CH ₂ - is a group having the following structure:

In one embodiment, R ¹ is (3-6C cycloalkyl)-CH ₂ -. Specific examples include cyclopropylmethyl and cyclohexylmethyl groups each having the following structure:

In one embodiment, R ¹ is (3-6C cycloalkyl)-CH ₂ -, hetCyc ¹ CH ₂ -, Ar ¹ (CH ₂ ) _n - or (N-1-3C alkyl) pyridinone- CH ₂ -.

In one embodiment, R ¹ is hetCyc ¹ CH ₂ -, wherein hetCyc ¹ is a 6-membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, optionally as -C(=O) (1-6C alkyl) or -C(=O)O(1-6C alkyl) substituted. Examples of hetCyc ¹ include a tetrahydropyranyl group, a piperidinyl group, and a morpholinyl ring. In one embodiment, hetCyc ^{1 is} optionally substituted with -C(=O)CH ₃ or -C(=O)OC(CH ₃ ) ₃ .

When represented by hetCyc ¹ CH ₂ -, a specific example of R ¹ includes the following structure:

In one embodiment, R ¹ is Ar ¹ (CH ₂ ) _n —, wherein Ar ¹ is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, (1-6C) Alkyl, CN, CF ₃ , OH, (1-6C) alkoxy, -C(=O)OH, -C(=O)O(1-6C alkyl), -C(=O)NR ^a R ^b or benzyloxy.

In one embodiment, R ¹ is Ar ¹ (CH ₂ ) _n —, wherein Ar ¹ is phenyl substituted with one or more substituents independently selected from the group consisting of F, Cl, methyl, CN , CF ₃ , OH, methoxy, -C(=O)OH, -C(=O)OCH ₃ , -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O N(CH ₃ ) ₂ or benzyloxy.

In one embodiment, n is zero. In one embodiment, n is one. In one embodiment, n is two.

When represented by Ar ¹ (CH ₂ ) _n -, a specific example of R ¹ includes the following structure:

In one embodiment, R ¹ is N-(1-3C alkyl)pyridinyl-CH ₂ -, that is, pyridinyl-CH ₂ - substituent, wherein the nitrogen ring atom of the pyridone group is (1) -3C) alkyl substitution. A specific example of R ¹ is the following structure:

In one embodiment, R ⁵ is H.

In one embodiment, R ⁵ is halogen. In one embodiment, R ⁵ is F or Br.

In one embodiment, R ⁵ is CN.

In one embodiment, R ⁵ is OH.

In one embodiment, R ⁵ is hetAr ⁴ , wherein hetAr ⁴ is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, wherein the ring is optionally one or more Substituent independently selected from (1-6C)alkyl and [di(1-3C alkyl)amino]CH ₂ -. In one embodiment, at least one of the ring heteroatoms is nitrogen. In embodiments where at least one of the ring heteroatoms is nitrogen, hetAr ⁴ can be a nitrogen group (ie, hetAr ⁴ is attached to the imidazopyridine ring of Formula I via a ring nitrogen atom of hetAr ⁴ ) or a carbon group ( That is, hetAr ⁴ is attached to the imidazopyridine ring of formula I via a ring carbon atom of hetAr ⁴ . Examples of hetAr ⁴ include pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl and furanyl rings, which are optionally independently selected from (1-6C)alkyl and [di(1) Substituent of -3C alkyl)amino]CH ₂ -. In certain embodiments, hetAr ^{4 is} optionally substituted with one or both of the substituents. In certain embodiments, hetAr ^{4 is} optionally substituted with one or two substituents independently selected from methyl and Me ₂ NCH ₂ -. When represented by hetAr ⁴ , a specific example of R ⁵ includes the following structure:

In one embodiment, R ⁵ is hetAr ⁴ , wherein hetAr ⁴ is a 5-membered heteroaryl ring having 2 ring nitrogen atoms, wherein the ring is optionally selected from one or more (1-6C) alkyl groups. Substituent substitutions, for example one or more substituents independently selected from (1-4C)alkyl (such as methyl). In one embodiment, the hetAr ⁴ is selected from the group consisting of:

In one embodiment, R ⁵ is hetAr ⁵ , wherein hetAr ⁵ is a 6-membered heteroaryl ring having 1-2 ring N atoms, optionally optionally selected from (1-6C)alkyl via one or more The substituent is substituted. Examples of hetAr ⁵ include a pyrimidinyl group and a pyridyl ring, which are optionally substituted with a substituent selected from (1-6C alkyl), for example, one or more independently selected from (1-4C) alkyl groups (e.g., methyl or ethyl) The substituent of the group is substituted. When represented by hetAr ⁵ , a specific example of R ⁵ includes the following structure:

In one embodiment, R ⁵ is hetAr ⁵ , wherein hetAr ⁵ is optionally substituted with one or more substituents independently selected from (1-6C)alkyl, for example one or more independently selected from (1-4C) A pyridyl group substituted with a substituent of an alkyl group such as methyl or ethyl. In one embodiment, hetAr ⁵ is a pyridyl group optionally substituted with a methyl group. In one embodiment, hetAr ⁵ is:

In one embodiment, R ⁵ is hetCyc ² , wherein hetCyc ² is a 5-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 ring heteroatoms selected from N and O, wherein the cyclic Substituting a plurality of substituents independently selected from the group consisting of (1-6C)alkyl, hydroxy(1-4C)alkyl, OH and pendant oxy groups, with the proviso that the pendant oxy group is on a carbon atom. In one embodiment, at least one of the ring heteroatoms of hetCyc ² is N. In one embodiment, when hetCyc ² comprises at least one N ring atom, hetCyc ² is a nitrogen group, that is, hetCyc ² is attached to the imidazopyridine ring of formula I via a ring nitrogen atom of hetCyc ² . In one embodiment, when hetCyc ² comprises at least one N ring atom, hetCyc ² is a carbon group, that is, hetCyc ² is attached to the imidazopyridine ring of formula I via a ring carbon atom of hetCyc ² . Examples of hetCyc ² include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyridyl and diazepanyl rings, which are optionally independently selected from one or more (1-6C) Substituents for alkyl, hydroxy (1-4C) alkyl, OH and pendant oxy groups. In certain embodiments, hetCyc ² is substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, OH, HOCH ₂ CH ₂ -, and pendant oxy groups. In one embodiment, hetCyc ^{2 is} optionally substituted with one or both of the substituents.

In one embodiment, when represented by hetCyc ² , examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is hetCyc ² , wherein hetCyc ² is a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 ring nitrogen atoms. In one embodiment, hetCyc ² is selected from the following structures:

In one embodiment, R ⁵ is hetCyc ³ (1-4C alkyl)-, wherein hetCyc ³ is a 4-6 membered heterocyclic ring having 1-2 ring N atoms, optionally selected by one or more Substituted from a substituent of (1-6C)alkyl, (1-6C)alkoxy and halogen. Examples of hetCyc ³ include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ring, which is optionally substituted with one or more groups independently selected from (1-6C) alkyl, (1 -6C) Substituted by alkoxy and halogen substituents. In one embodiment, hetCyc ^{3 is} optionally substituted with one or more substituents independently selected from the group consisting of (1-4C)alkyl, (1-6C)alkoxy, and halogen. In certain embodiments, hetCyc ³ is substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, fluoro, and methoxy. In certain embodiments, hetCyc ³ is substituted with one or both of the substituents. In certain embodiments, R ⁵ is hetCyc ³ (1-3C)alkyl. When represented by hetCyc ³ (1-4C alkyl)-, specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is hetCyc ³ (1-4C alkyl)-, wherein hetCyc ³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc ³ Substituted by a substituent selected from a (1-6C) alkyl group. In one embodiment, the hetCyc ³ (1-4C alkyl)- is selected from the following structures:

In one embodiment, R ⁵ is hetCyc ⁴ (1-4C) alkoxy, i.e., defined herein as the (1-4C) alkoxy, wherein one carbon atom is substituted with hetCyc ^4, wherein hetCyc ⁴ a 4-7 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O and S, wherein one of the ring nitrogen atoms is optionally oxidized to N(O) and wherein the S ring atom Oxidized to SO or SO _{2 as appropriate} , wherein hetCyc ^{4 is} optionally selected from one or more selected from the group consisting of halogen, OH, (1-6C)alkyl, (1-4C alkoxy)(1-6C)alkyl, Substituent substitution of (1-4C)alkyl-OC(=O)- and (1-6C)alkoxy. Examples of hetCyc ⁴ include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, diazepanyl, 1-methyl-piperazinyl-1-oxide and Thimorpholinyl-1,1-dioxide, each of which is optionally independently selected from halo, OH, (1-6C)alkyl, (1-4C alkoxy) (1-6C) Substituent substitution of alkyl, (1-4C)alkyl-OC(=O)- and (1-6C)alkoxy. In certain embodiments, hetCyc ^{4 is} optionally independently selected from the group consisting of methyl, ethyl, isopropyl, fluoro, methoxy, CH ₂ OCH ₂ CH ₂ -, OH, and (CH ₃ ) ₃ Substituent substitution of COC(=O)-. In certain embodiments, hetCyc ^{4 is} optionally substituted with one to three of the substituents. In certain embodiments, R ⁵ is hetCyc ⁴ (1-2C) alkoxy.

In one embodiment, when represented by hetCyc ⁴ (1-4C) alkoxy, examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is hetCyc ⁴ (1-4C) alkoxy, i.e., defined herein as the (1-4C) alkoxy, wherein one carbon atom is substituted with hetCyc ^4, wherein hetCyc ⁴ Is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein the ring is optionally selected from (1-6C)alkyl, (1-4C alkoxy) by one or more Substituent substitution of (1-6C)alkyl and (1-4C)alkyl-OC(=O)-. In one embodiment, hetCyc ⁴ optionally has 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, isopropyl, CH ₃ OCH ₂ CH ₂ -, and (CH ₃ ) ₃ COC(=O)- Replace. In one embodiment, when represented by hetCyc ⁴ (1-4C) alkoxy, examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is hetCyc ⁵ (1-4C) alkoxy, i.e., as the (1-4C) alkoxy as defined herein, wherein one carbon atom is substituted with hetCyc ^5, wherein hetCyc ⁵ It is a spiroheterocycle having 2 ring heteroatoms independently selected from N and O, and is optionally substituted with a substituent selected from a (1-6C) alkyl group. The term "spiroheterocycle" as used herein refers to a system comprising two rings, one of which is a nitrogen-containing heterocycle having a common carbon atom, such as 2-oxa-6-, respectively having the structure Azaspiro[3.3]heptane or 2,6-diazaspiro[3.3]heptane ring system:

In one embodiment, hetCyc ^{5 is} optionally substituted with a group selected from (1-6C)alkyl (eg, methyl).

In one embodiment, when represented by hetCyc ⁵ (1-4C) alkoxy, examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is (1-3C alkoxy)(1-4C)alkoxy, that is, a (1-4C) alkoxy group, as defined herein, wherein one carbon atom is Substituted by a 1-3C alkoxy) substituent such as methoxy. When represented by (1-3C alkoxy)(1-4C)alkoxy, specific examples of R ⁵ include a methoxyethoxy substituent having the following structure:

In one embodiment, R ⁵ is hydroxy(1-6C)alkoxy, that is, (1-6C)alkoxy, wherein one carbon atom is substituted with a hydroxy group. In one embodiment, R ⁵ is hydroxy(1-4C)alkoxy. When represented by a hydroxy(1-6C)alkoxy group, specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is a dihydroxy (2-6C) alkoxy group, that is, a (2-6C) alkoxy group, wherein each of the two carbon atoms is substituted with a hydroxy group. In one embodiment, R ⁵ is a dihydroxy (2-4C) alkoxy group. When represented by a dihydroxy (2-6C) alkoxy group, a specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is (1-6C)alkoxy. In one embodiment, R ⁵ is (1-4C)alkoxy. In one embodiment, R ⁵ is methoxy or ethoxy.

In one embodiment, R ⁵ is [hydroxy(2-4C)alkyl)amino](1-4C)alkyl, that is, (1-4C)alkyl, one of which is via [hydroxyl (2) -4C alkyl)]amino substituent, for example, HOCH ₂ CH ₂ NH-substituent. A specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is [(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl, ie, (1-4C)alkyl, one of which is carbon The atom is substituted with a [(1-4C alkoxy)(1-4C alkyl)amino substituent, such as a methoxy (1-4C alkyl) NH- substituent. When represented by [(1-4C alkoxy)(1-4C alkyl)]amino(1-4C)alkyl, a specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is [di(1-4C alkyl)amino](1-4C)alkyl, that is, (1-4C)alkyl, wherein one carbon atom is passed through two (1-4C) Alkyl) amine group substitution. In one embodiment, R ⁵ is dimethylamino (1-4C alkyl). When R ⁵ is [di(1-4C alkyl)amino](1-4C)alkyl, specific examples include the following structures:

In one embodiment, R ⁵ is (1-4C alkyl)C(=O)-. Specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is hydroxy(1-6C)alkyl, that is, (1-6C)alkyl as defined herein, wherein one carbon atom is substituted with a hydroxy group. In one embodiment, R ⁵ is hydroxy(1-4C)alkyl. Specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is dihydroxy(2-6C)alkyl, that is, (1-6C)alkyl as defined herein, wherein each of the two carbon atoms is substituted with a hydroxy group. In one embodiment, R ⁵ is a dihydroxy (2-4C) alkyl group. A specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is [di(1-3C alkyl)amino](1-4C)alkoxy, that is, (1-4C) alkoxy, wherein one carbon atom is passed through two (1) a -3C alkyl)amino group, such as a dimethylamino group. When represented by [di(1-3C alkyl)amino](1-4C)alkoxy, specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is N-(1-3C alkyl)pyridone. Specific examples include N-methylpyridone, which can be represented by the following structure:

In one embodiment, R ⁵ is hetAr ^6, wherein hetAr ⁶ is a portion 9 having 3 ring N atoms of an unsaturated bicyclic heterocyclic ring which is optionally substituted with one or more groups independently selected from (1-6C) alkyl The substituent is substituted. Examples of hetAr ⁶ include a 5-membered heteroaryl ring fused to a 6-membered saturated heterocyclic ring, wherein one or both of the rings are optionally substituted with a group independently selected from (1-6C alkyl). Specific examples include a 5,6,7,8-tetrahydroimidazopyrazine ring which is optionally substituted with a substituent selected from (1-6C alkyl), for example one or more independently selected from (1-4C) alkane Substituents such as methyl or ethyl are substituted. When expressed as hetAr ⁶ , the specific value of R ⁵ includes the following structure:

In one embodiment, R ⁵ is hetCyc ⁶ C(=O)-, wherein hetCyc ⁶ is a 6-membered heterocyclic ring having 1-2 ring N atoms, optionally selected from one or more independently selected from the group consisting of 1- 6C) Substituent substitution of an alkyl group. Examples of hetCyc ⁶ include piperidinyl and piperazinyl rings, optionally selected from one or more alkyl groups selected from (1-6C)alkyl, such as (1-4C)alkyl (such as methyl or ethyl). Substituent substitution. When represented by hetCyc ⁶ C(=O)-, a specific example of R ⁵ includes the following structure:

In one embodiment, R ⁵ is (hetCyc ⁷ )-O-, wherein hetCyc ⁷ is a 4-6 membered heterocyclic ring having one or two ring N atoms, optionally selected from one or more independently (1) -6C) Substituent substitution of alkyl and OH. Examples of hetCyc ⁷ include azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl rings, which are optionally substituted with one or more substituents independently selected from (1-6C)alkyl and OH. In certain embodiments, hetCyc ⁷ is azetidinyl, pyrrolidinyl or piperidinyl, optionally substituted with one or more substituents independently selected from methyl and OH. In certain embodiments, hetCyc ⁷ is substituted with one or both of the substituents. When represented by (hetCyc ⁷ )-O-, a specific example of R ⁵ includes the following structure:

In one embodiment, R ⁵ is hetCyc ⁸ (1-4C) alkoxy, i.e., defined herein as the (1-4C) alkoxy, wherein one carbon atom is substituted with hetCyc ^8, wherein hetCyc ⁸ Is a bridged 8-membered heterocyclic ring having 2 ring atoms selected from N and O, wherein at least one of the heteroatoms is N, wherein the ring is optionally substituted with a (1-6C) alkyl group. Examples of the hetCyc ⁸ ring include 3,8-diazabicyclo[3.2.1]octane and 8-oxa-3-azabicyclo[3.2.1]octane ring, which may be as appropriate (1-6C). Alkyl substitution. When represented by hetCyc ⁸ (1-4C) alkoxy, specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is a difluoroamino (1-4C) alkoxy group, that is, a (1-4C) alkoxy group, as defined herein, wherein alkoxy is as defined herein. A portion of one of the hydrogen atoms is replaced by an amine group, and each of the two hydrogen atoms of the alkoxy moiety as defined herein is replaced by a fluorine atom. When represented by a difluoroamino (1-4C) alkoxy group, a specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is [(1-4C alkoxy)carbonylguanamine]difluoro(1-4C)alkoxy, that is, (1-4C) alkoxy as defined herein. Wherein two carbon atoms are each substituted by a fluorine atom and one carbon atom is substituted by a (1-4C alkoxy)carbonylguanamine such as a (CH ₃ ) ₃ OC(=O)NH- group. When represented by [(1-4C alkoxy)carbonylguanamine]difluoro(1-4C)alkoxy, a specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is (1-4C alkyl)C(=O)NH(2-4C)alkylthio-, ie, (2-4C)alkylthio, wherein the group is in sulfur At the atom, one of the carbon atoms is substituted with a (1-4C alkyl) C(=O)NH- substituent. When represented by a (1-4C alkyl)C(=O)NH(2-4C)alkylthio group, specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is (1-4C alkyl)OC(=O)-. A specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is R ^c R ^d NC(=O)-, wherein R ^c is H or methyl and R ^d is (1-4C)alkyl, hetCyc ¹⁰ -, amine (1-4C) An alkyl group or [di(1-4C alkyl)amino](1-4C alkyl). In one embodiment, R ^c is H. In one embodiment, R ^c is methyl.

In one embodiment, R ⁵ is R ^c R ^d NC(=O)-, wherein R ^c is H or methyl and R ^d is hetCyc ¹⁰ . Examples of the hetCyc ¹⁰ group include a pyrrolidinyl ring which is optionally substituted with a (1-6C)alkyl group such as a (1-4C)alkyl group such as methyl or ethyl. Specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is R ^c R ^d NC(=O)-, wherein R ^c is H or methyl and R ^d is an amine (1-4C) alkyl group. A specific example of R ⁵ is the following structure:

In one embodiment, R ⁵ is R ^c R ^d NC(=O)-, wherein R ^c is H or methyl and R ^d is [di(1-4C alkyl)amino](1-4C)alkane base-. In one embodiment, R ^d is dimethylamino (1-4C alkyl). Specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is R ^c R ^d NC(=O)-, wherein R ^c is H or methyl and R ^d is (1-4C)alkyl. Specific examples of R ⁵ include the following structures:

In one embodiment, R ⁵ is selected from the group consisting of H, halogen, CN, OH, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ (1-4C alkyl)-, hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy, (1-3C alkoxy) (1-4C) alkoxy, hydroxy (1-6C) alkoxy, dihydroxy (2-6C) alkoxy, ( 1-4C) alkoxy group, [hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4C alkyl)amino]( 1-4C) alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl, Dihydroxy (2-6C) alkyl, [bis(1-3C alkyl)amino](1-4C)alkoxy and N-(1-3C alkyl)pyridone.

In certain embodiments, R ⁵ is selected from the group consisting of H, halogen, CN, and OH.

In certain embodiments, R ⁵ is selected from the group consisting of hetAr ⁴ , hetAr ⁵ , hetCyc ^{2 ,} and hetCyc ³ (1-4C alkyl)-.

In certain embodiments, the R ⁵ is selected from the group consisting of hetAr ⁴ or hetAr ⁵ .

In certain embodiments, R ⁵ is selected from the group consisting of hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy, (1-3C alkoxy) (1-4C) alkoxy A hydroxy(1-6C)alkoxy group, a dihydroxy(2-6C)alkoxy group, a (1-4C) alkoxy group, and a 3C alkyl)amino](1-4C)alkoxy group.

In certain embodiments, the R ⁵ is selected from the group consisting of hetCyc ² or hetCyc ³ (1-4C alkyl)-.

In certain embodiments, R ⁵ is hetCyc ⁴ (1-4C) alkoxy or hetCyc ⁵ (1-4C) alkoxy.

In certain embodiments, R ⁵ is hetCyc ⁴ (1-4C) alkoxy.

In certain embodiments, R ⁵ is (1-3C alkoxy)(1-4C)alkoxy.

In certain embodiments, R ⁵ is selected from the group consisting of (1-3C alkoxy)(1-4C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, (1-6C) alkoxy group, [hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4C alkyl)amino] (1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl Dihydroxy (2-6C) alkyl and [di(1-3C alkyl)amino](1-4C)alkoxy.

In certain embodiments, R ⁵ is selected from the group consisting of [hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4C alkyl) Amino](1-4C)alkyl, [bis(1-4C alkyl)amino](1-4C)alkyl, hydroxy(1-4C)alkyl and dihydroxy(2-4C)alkyl.

In certain embodiments, R ⁵ is selected from ^{hetAr 6, hetCyc 6 C (=} O) -, (hetCyc 7) -O-, hetCyc 8 (1-4C) alkoxy, difluoromethyl group (1- 4C) alkoxy, [(1-4C alkoxy)carbonylguanamine]difluoro(1-4C)alkoxy, (1-4C alkyl)C(=O)NH(2-4C)alkylsulfide Base-, (1-4C alkyl)OC(=O)- and R ^c R ^d NC(=O)-.

In certain embodiments of formula I , R ² is H.

In certain embodiments of formula I , R ² is CH ₃ .

In certain embodiments of Formula I , R ² is F.

In certain embodiments of formula I , R ² is Cl.

In certain embodiments of formula I , R ² is H or CH ₂ .

In certain embodiments of Formula I , R ³ is H.

In certain embodiments of Formula I , R ³ is F.

In certain embodiments of formula I , R ³ is Cl.

In certain embodiments of formula I , R ⁴ is H.

In certain embodiments of Formula I , R ⁴ is CN.

In certain embodiments of Formula I , R ⁴ is F.

In certain embodiments of formula I , R ⁴ is Cl.

In certain embodiments of formula I , R ⁴ is Br.

In certain embodiments of Formula I , R ⁴ is -OM _e .

In certain embodiments of formula I , R ⁴ is -OCF ₃ .

In certain embodiments of formula I , R ⁴ is -CF ₃ .

In certain embodiments of formula I , R ⁴ is -CH(OH)CH ₂ OH.

In certain embodiments of formula I , R ⁴ is -C(=O)NH ₂ .

In certain embodiments of formula I , R ⁴ is selected from the group consisting of H, CN, Br, -OMe, -CH(OH)CH ₂ OH, or -C(=O)NH ₂ .

In certain embodiments of Formula I , R ⁶ is H.

In certain embodiments of formula I , R ⁶ is Cl.

In certain embodiments of formula I , R ³ , R ⁴ , R ⁵ and R ⁶ are H.

In one embodiment of formula I , R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ -, hetAr ³ CH ₂ -, (3-6C cycloalkyl)-CH ₂ -, hetCyc ¹ CH ₂ -, Ar ¹ (CH ₂ ) _n - or (N-1-3C alkyl)pyridinyl-CH ₂ -; R ² is H, F, Cl or CH ₃ ; R ³ is H, F or Cl; ⁴ is H, CN, Br, -OMe, -CH(OH)CH ₂ OH or -C(=O)NH ₂ ; R ⁵ is selected from H, halogen, CN, OH, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ (1-4C alkyl) -, hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy, (1-3C alkoxy) (l-4C) alkoxy , hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, (1-6C)alkoxy, [hydroxy(2-4C)alkyl)amino]-(1-4C) Alkyl, [(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl, [bis(1-4C alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di(1-3C alkyl)amino](1-4C) Alkoxy and N-(1-3C alkyl)pyridone; and R ⁶ is H or Cl; wherein m, hetAr ¹ , hetAr ² , hetAr ³ , hetCyc ¹ , Ar ¹ , n, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ , hetCyc ⁴ and hetCyc ^{5 are} as defined for formula I.

In one embodiment of Formula I , R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ -; R ² is F, Ck, H or CH ₃ ; R ³ is H; R ⁴ is H; R ⁵ is selected from the group consisting of H, halogen, CN, OH, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ (1-4C alkyl)-, hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy, (1-3C alkoxy)(1-4C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, (1 -6C) alkoxy, [hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4C alkyl)amino](1 -4C) alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl, two a hydroxy (2-6C) alkyl group, a [bis(1-3C alkyl)amino](1-4C)alkoxy group and an N-(1-3C alkyl)pyridinone; and R ⁶ is H; wherein m ^{, hetAr 1, hetAr 2, hetAr} 3, hetAr 4, hetAr 5, hetCyc 2, hetCyc 3, hetCyc 4 and hetCyc ⁵ as defined for formula I.

In one embodiment of Formula I , R ¹ is hetAr ¹ (CH ₂ ) _m -; R ² is F, Cl, H or CH ₃ ; R ³ is H; R ⁴ is H; R ⁵ is selected from H, Halogen, CN, OH, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ (1-4C alkyl)-, hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy, (1 -3C alkoxy) (1-4C) alkoxy, hydroxy (1-6C) alkoxy, dihydroxy (2-6C) alkoxy, (1-6C) alkoxy, [hydroxy (2- 4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl, [di(1-4C) Alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di( 1-3C alkyl)amino](1-4C)alkoxy and N-(1-3C alkyl)pyridone; and R ⁶ is H; wherein m, hetAr ¹ , hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ , hetCyc ⁴ and hetCyc ^{5 are} as defined for formula I.

In one embodiment of Formula I , R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ -; R ² is F, Cl, H or CH ₃ ; R ³ is H; R ⁴ is H; R ⁵ is hetCyc ⁴ (1-4C) alkoxy or hetCyc ⁵ (1-4C) alkoxy; and R ⁶ is H; wherein m, hetAr ¹ , hetAr ² , hetAr ³ , hetCyc ⁴ and hetCyc ⁵ as defined for formula I.

In one embodiment of Formula I , R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ ; R ² is CH ₃ ; R ³ is H; R ⁴ is H; R ⁵ Is hetCyc ⁴ (1-4C) alkoxy or hetCyc ⁵ (1-4C) alkoxy; and R ⁶ is H; wherein m, hetAr ¹ , hetAr ² , hetAr ³ , hetCyc ⁴ and hetCyc ^{5 are} as for Formula I Defined.

In one embodiment of Formula I , R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ ; R ² is F, Cl, H or CH ₃ ; R ³ is H; ⁴ is H; R ⁵ is hetAr ⁴ or hetAr ⁵ ; and R ⁶ is H; wherein m, hetAr ¹ , hetAr ² , hetAr ³ , hetAr ⁴ and hetAr ^{5 are} as defined for formula I.

In one embodiment of Formula I , R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ ; R ² is F, Cl, H or CH ₃ ; R ³ is H; ⁴ is H; R ⁵ is hetCyc ² or hetCyc ³ (1-4C alkyl)-; and R ⁶ is H; wherein m, hetAr ¹ , hetAr ² , hetAr ³ , hetCyc ² and hetCyc ^{3 are} as defined for formula I .

In one embodiment of formula I , R ¹ is (3-6C cycloalkyl)-CH ₂ -, hetCyc ¹ CH ₂ -, Ar ¹ (CH ₂ ) _n - or (N-1-3C alkyl)pyridine Keto-CH ₂ -; R ² is F, Cl, H or CH ₃ ; R ³ is H; R ⁴ is H; R ⁵ is selected from H, halogen, CN, OH, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ (1-4C alkyl)-, hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy, (1-3C alkoxy) (1-4C) alkoxy , hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, (1-6C)alkoxy, [hydroxy(2-4C)alkyl)amino]-(1-4C) Alkyl, [(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl, [bis(1-4C alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di(1-3C alkyl)amino](1-4C) Alkoxy and N-(1-3C alkyl)pyridone; and R ⁶ is H; wherein hetCyc ¹ , Ar ¹ , n, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ , hetCyc ⁴ and hetCyc ⁵ Defined by Formula I.

In one embodiment, Formula I does not include the following compound: 3-((4-(7-(2-methoxyethoxy))imidazo[1,2-a]pyridine-3-carboxamido) -1H-carbazol-1-yl)methyl)benzoic acid and 7-(2-methoxyethoxy)-N-(1-(piperidin-4-ylmethyl)-1H-carbazole- 4-yl)imidazo[1,2-a]pyridine-3-carboxamide.

The terms "(1-6C)alkyl", "(1-4C)alkyl", "(2-4C)alkyl" and "(2-6C)alkyl" as used herein mean 1 respectively. A saturated linear or branched chain monovalent hydrocarbon group of up to 6 carbon atoms, 1 to 4 carbon atoms, 2 to 4 carbon atoms or 2 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, second butyl, tert-butyl, 2-methyl-2-propyl, Amyl and hexyl.

The terms "(1-6C)alkoxy", "(1-4C)alkoxy", "(2-4C)alkoxy" and "(2-6C)alkoxy" as used herein, respectively By a saturated straight or branched chain monovalent alkoxy group having from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 2 to 4 carbon atoms or from 2 to 6 carbon atoms, wherein the group is on the oxygen atom . Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.

When a substituent is described using a chemical formula, the dashed line on the left or right side of the formula indicates that the free valence is on the left or right side portion of the substituent, respectively.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

It will be understood that certain compounds according to the invention may contain one or more asymmetric centers and may therefore be in the form of a mixture of isomers (such as racemic or diastereomeric mixtures) or enantiomerically pure or Preparation and separation in diastereomerically pure form. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof (such as racemic mixtures), form the present invention. portion.

The reaction products are preferably separated from each other and/or separated from the starting materials. The desired product in each step or series of steps is separated and/or purified (hereinafter separated) by the techniques commonly employed in the art to the desired degree of homogeneity. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography can involve a variety of methods including, for example, reversed phase and normal phase; size exclusion; ion exchange; high pressure, medium pressure and low pressure liquid chromatography and equipment; small scale analysis; simulated moving bed ("SMB") and preparation Thin layer or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art will employ the techniques most likely to achieve the desired separation.

The enantiomers can be separated by the reaction of a suitable optically active compound (for example, a palmitic auxiliary such as palmitic alcohol or Mosher's acid chloride). The isomeric mixture is converted to a diastereomeric mixture, the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Enantiomers can also be separated using a palm-shaped HPLC column. The diastereomeric mixture can be separated into individual diastereomers by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization, depending on physicochemical differences.

The chiral mixture can be resolved by methods known in the art to obtain a single stereoisomer (e.g., enantiomer) substantially free of its stereoisomers, such as (1) Forming an ionic diastereomeric salt to a palm compound and separating it by fractional crystallization or other methods; (2) Forming a diastereomeric compound with a palmitic derivatizing reagent, separating the diastereomers And conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers directly under palmar conditions. See: Wainer, Irving W., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

According to the method (1), by such things as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenyl B The enantiomerically pure amine (amphetamine) and its analogs react with a palmitic base with an asymmetric compound having an acidic functional group such as a carboxylic acid and a sulfonic acid to form a diastereomeric salt. These diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. To separate the optical isomers of the amine based compound, the addition of a palmitic carboxylic acid or a sulfonic acid, such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid, can result in the formation of diastereomeric salts.

Alternatively, according to method (2), the substrate to be resolved is reacted with an enantiomer of the palm compound to form a diastereomeric pair (Eliel, E. and S. Wilen. Stereochemistry of Organic Compounds . New York: John Wiley & Sons , Inc., 1994, p. 322). A diastereomeric compound can be formed by reacting an asymmetric compound with an enantiomerically pure palmitic derivatizing reagent such as a menthol derivative, followed by separation of the diastereomer and hydrolysis to yield a pure Or enriched enantiomers. The method for determining optical purity involves the preparation of a palmitic ester of a racemic mixture, such as menthol ester, such as (-) menthol chloroformate (in the presence of a base) or moiré ester, i.e., alpha-a Oxy-α-(trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity. J. Org. Chem. , Vol . 47, No. 21 (1982): pp. 4165-4167) and analysis of two atropisomer enantiomers or diastereoisomers in ¹ H NMR spectra The existence of things. Stable diastereomers of atropisomeric compounds can be separated and separated by normal phase and reverse phase chromatography following the method for the separation of atropisomeric naphthyl-isoquinolines (WO 96/15111) .

According to the method (3), a racemic mixture of two enantiomers can be separated by chromatography using a palmitic stationary phase (Lough, WJ, Chiral Liquid Chromatography . New York: Chapman and Hall, 1989; Okamoto, Yoshio et al., "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase." J. of Chromatogr. Vol. 513 (1990): 375-378). Enriched or purified enantiomers can be identified by methods for identifying other pairs of palmitic molecules having asymmetric carbon atoms, such as optical rotation and circular dichroism.

In one embodiment, the degree of enrichment of one enantiomer of a compound of Formula I relative to the other enantiomer can be up to 80% enantiomeric excess. In one embodiment, the degree of enrichment of one enantiomer of a compound of Formula I relative to the other enantiomer can be up to 85% enantiomeric excess. In one embodiment, the degree of enrichment of one enantiomer of a compound of Formula I relative to the other enantiomer can be up to 90% enantiomeric excess. In one embodiment, the degree of enrichment of one enantiomer of a compound of Formula I relative to the other enantiomer can be as high as 95% enantiomeric excess.

The term "enantiomeric excess" as used herein refers to the absolute difference between the molar fractions of the individual enantiomers.

It will be further understood that the enantiomers of the compounds of the invention can be prepared by starting with a suitable starting material for the palm.

In the structures shown herein, all stereoisomers are encompassed and included as compounds of the invention without specifically specifying the stereochemistry of any particular pair of palm atoms. Where stereochemistry is specified by a solid wedge or dashed line indicating a particular configuration, the stereoisomeric system is specifically illustrated and defined in this manner.

It will also be understood that certain compounds of formula I are useful as intermediates in the preparation of other compounds of formula I.

The compounds of formula I include the salts thereof. In certain embodiments, the salts are pharmaceutically acceptable salts. Furthermore, the compounds of the formula I include the other salts of the compounds, which are not necessarily pharmaceutically acceptable salts and which are useful as intermediates for the preparation and/or purification of the compounds of the formula I and/or for the isolation of the compounds of the formula I The intermediate.

It is to be further understood that the compounds of formula I and their salts can be isolated in the form of solvates, and thus any such solvates are included within the scope of the invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compounds. That is, an atom (especially when referenced to a compound of formula I ) encompasses all isotopically and isotopic mixtures of the atom produced naturally or synthetically, which have a natural abundance or an isotopically enriched form. By way of example, when referring to hydrogen, it is understood to mean ¹ H, ² H, ³ H or mixtures thereof; when referring to carbon, it is understood to mean ¹¹ C, ¹² C, ¹³ C, ¹⁴ C or a mixture thereof; when referring to nitrogen, it is understood to mean ¹³ N, ¹⁴ N, ¹⁵ N or a mixture thereof; when referring to oxygen, it is understood to mean ¹⁴ O, ¹⁵ O, ¹⁶ O, ¹⁷ O, ¹⁸ O or a mixture thereof; and when referring to fluorine, it is understood to mean ¹⁸ F, ¹⁹ F or a mixture thereof. Thus, a compound according to the invention also comprises a compound having one or more isotopes of one or more atoms, and mixtures thereof, including one or more radioactive compounds in which the non-radioactive atom has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds can be used as therapeutic agents, such as cancer therapeutics, research reagents (e.g., analytical reagents), and diagnostic reagents (e.g., in vivo imaging reagents). All isotopic variations of the compounds of the invention, whether or not they are radioactive, are intended to be encompassed within the scope of the invention.

The invention further provides a process for the preparation of a compound of formula I, or a salt thereof, as defined herein, the process comprising:

(a) making the corresponding compound of formula II

Wherein Z ¹ is COOH or a reactive derivative thereof; and the corresponding compound of formula III

Coupling in the presence of a coupling reagent; or

(b) bringing the corresponding compound of formula IV

Compound with formula III

Coupling in the presence of a base; or

(c) for R ⁵ is hetCyc ⁴ (1-4C) alkoxy, (hetCyc ⁷ )-O-, hetCyc ⁸ (1-4C) alkoxy, hydroxy (1-6C) alkoxy, difluoroamine group (1-4C) alkoxy or [(l-4C-alkoxy) carbonyl Amides] difluoro (1-4C) alkoxy the compound of formula I, that the corresponding compounds of formula V

Wherein X ¹ is F or Cl; and a compound having the formula R ^5a -O- (wherein R ^{5a is} correspondingly hetCyc ⁴ (1-4C) alkyl-OH, hetCyc ⁷ -OH, hetCyc ⁸ (1-4C) alkane -OH, P ¹ O-(1-6C)alkyl-OH, difluoroamino (1-4C)alkyl-OH or [(1-4C alkoxy)carbonylguanamine]difluoro(1- 4C) an alkyl-OH) is reacted in the presence of a base, wherein P ¹ is a hydroxy protecting group;

(d) for a compound of formula I wherein R ⁵ is hetCyc ² (wherein hetCyc ² is a nitrogen group), the corresponding compound of formula Va is rendered

Reacting with a compound having the formula hetCyc ² -H; or

(e) for a compound of formula I wherein R ⁵ is hetAr ⁴ (where hetAr ⁴ is a nitrogen group), the corresponding compound of formula Va is rendered

Reacting with a compound having the formula hetAr ⁴ -H in the presence of a base; or

(f) for R ⁵ is selected from hetAr ^4, hetAr ⁵ and N- (1-3C-alkyl) connected to the carbon substituted pyridone group of compounds of formula I, a compound corresponding to formula Vb

And compounds having formula VI

Wherein ring E is correspondingly a carbon linking group selected from the group consisting of hetAr ⁴ , hetAr ⁵ and N-(1-3C alkyl) pyridone; reacted in the presence of a palladium catalyst and a base;

(g) for a compound of formula I wherein R ⁵ is hetAr ⁴ or hetAr ⁶ (wherein hetAr ⁴ and hetAr ⁶ are carbon groups), the corresponding compound of formula Vb is rendered

Reacting with a compound having the formula hetAr ⁴ -H or hetAr ⁶ -H, respectively, in the presence of a palladium catalyst and a base and optionally in the presence of a ligand;

(h) for a compound of formula I wherein R ⁵ is hetCyc ⁶ C(=O)-, having the corresponding compound of formula VII

Reacting with a compound having the formula hetCyc ⁶ -H in the presence of a coupling reagent; or

(i) a compound of formula I having the following structure for R ⁵ :

Making the corresponding compound of formula VIII

Where R ^{5b is} correspondingly

Reacting with formaldehyde in the presence of a reducing agent; or

(j) for a compound of formula I wherein R ⁵ is R ^c R ^d NC(=O)-, corresponding compound of formula IX

Reacting with a compound of the formula R ^c R ^d NH in the presence of a coupling agent; or

(k) a compound of formula I wherein R ⁵ is a oxadiazole substituent of the formula:

Wherein R ^g is H or Me; such that the corresponding compound of formula X is obtained

Cyclization in the presence of trimethoxymethane or triethoxyethane, respectively; or

(1) for a compound of formula I wherein R ⁵ is 1,3,4-thiadiazol-2-yl, the corresponding compound of formula XI is obtained

Cyclization in the presence of P ₂ S ₅ ; or

(m) for R ⁵ is hetCyc ³ (1-2C alkyl)-(wherein hetCyc ³ is a nitrogen group, [(1-4C alkoxy)(1-4C alkyl)]amino group (1-2C) alkane Or a compound of formula I , [hydroxy(2-4C)alkyl)]amino-(1-2C)alkyl), corresponding compound of formula XII

Wherein n is 0 or 1 and Z is H or Me; respectively with hetCyc ³ -H, [(1-4C alkoxy)(1-4C alkyl)]NH ₂ or [hydroxy(2-4C)alkyl) ] NH ₂ is reacted in the presence of a reducing agent; or

(n) a compound of formula I wherein R ¹ is hetAr ² CH ₂ - and hetAr ² is a pyrazolyl ring in which a ring N atom is substituted with a substituent selected from or (1-6C)alkyl-, such that it has the formula XIII Corresponding compound

Correspondingly reacting with a compound of the formula (1-6C)alkyl-X ² wherein X ² is a leaving group or atom in the presence of a base;

(o) for a compound of formula I wherein R ¹ is N-(1-3C alkyl)pyridinyl-CH ₂ -, corresponding compound of formula XIV

Coupling with (1-3C alkyl)-L ¹ (wherein L ¹ is a leaving group or atom) in the presence of a base;

(p) for a compound of formula I wherein R ⁵ is hetCyc ³ CH ₂ - (where hetCyc ³ is a nitrogen group), the corresponding compound of formula XV is obtained

Wherein L ² is a leaving group; coupling with a compound having the formula hetCyc ³ -H in the presence of a base; or

(q) a compound of formula I wherein R ⁵ is hetCyc ⁴ (1-4C) alkoxy and hetCyc ⁴ is N-methylpiperazine-1-oxide, the corresponding compound of formula XVI

Wherein n is 0, 1, 2 or 3; reacts with an oxidizing agent; or

(r) for a compound of formula I wherein R ⁵ is hetCyc ³ (1-4C alkyl)- (where hetCyc ³ is a nitrogen group), the corresponding compound of formula XVII is obtained

Wherein n is 0, 1, 2 or 3 and L ³ is a leaving group; reacting with a corresponding compound having the formula hetCyc ³ in the presence of a base;

(s) for a compound of formula I wherein R ⁵ is (1-4C alkyl)C(=O)NH(2-4C)alkylthio-, giving the corresponding compound of formula V

Wherein X ¹ is F or Cl; and a compound having a formula (1-4C alkyl) C(=O)NH(2-4C)alkyl-SH is coupled in the presence of a base;

(t) for a compound of formula I wherein R ⁵ is CH ₃ C(=O)-, giving the corresponding compound of formula Vb

And a compound having the formula

Coupling in the presence of a palladium catalyst and a ligand, followed by treatment with an acid; or

(u) for a compound of formula I wherein R ⁵ is HO(CH ₂ CH ₂ )-, treating the corresponding compound of formula XVIII with a reducing agent

And

Remove any protecting groups if necessary and form salts if necessary.

Referring to method (a), the coupling of a compound of formula II with a compound of formula III can be carried out using conventional guanamine bond forming conditions, for example by treating the carboxylic acid with an activator, followed by the addition of the amine in the presence of a base. Suitable active agents include chloroform, sulfoxide, EDCI, HATU and HOBt. Suitable bases include amine bases such as triethylamine, diisopropylethylamine, pyridine or excess ammonia. Suitable solvents include DCM, DCE, THF and DMF.

Alternatively, a guanamine linkage can be formed by coupling a reactive derivative of a carboxylic acid of formula II , such as an acid halide, such as an acid chloride, or a lithium salt thereof.

Referring to method (b), suitable bases include alkali metal hydrides such as NaH; alkali metal amine bases such as lithium diisopropylamide; and decyl metal amides such as sodium hexamethyldidecylamine Or lithium hexamethyldidecylamino).

Referring to method (c), suitable bases include alkali metal carbonates or alkoxides such as cesium carbonate or sodium tributoxide.

Referring to method (d), suitable solvents include toluene and THF. The reaction is usually carried out at a relatively high temperature (for example, a temperature between 110 ° C and 120 ° C).

Referring to method (e), suitable bases include alkali metal hydrides such as sodium hydride or potassium hydride. Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane), DMF or acetone. The reaction can generally be carried out at elevated temperatures (e.g., at temperatures ranging from 90 °C to 110 °C).

Referring to method (f), suitable palladium catalysts include Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ and Pd(OAc) ₂ . Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane), toluene or DMF. The reaction can generally be carried out at higher temperatures (e.g., at temperatures ranging from 70 °C to 90 °C).

Referring to method (g), suitable palladium catalysts include Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ and Pd(OAc) ₂ . Suitable ligands include trifuran-2-ylphosphine, rac-BINAP, DIPHOS, and the like. The base can be, for example, an alkali metal carbonate or an alkoxide such as cesium carbonate or sodium butoxide. Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane), toluene or DMF.

Referring to method (h), suitable coupling reagents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), DCC, 1,1'-carbonyldiimidazole (CDI) And its analogues.

Referring to method (i), suitable reducing agents include Na(OAc) ₃ BH and NaCNBH ₃ . Suitable solvents include neutral solvents such as acetonitrile, THF and dichloroethane.

Referring to method (j), examples of suitable coupling agents include CDI, EDCI, phosgene, and bis(trichloromethyl)carbonate. Suitable solvents include dichloromethane, dichloroethane, THF and DMF. The reaction is usually carried out at ambient temperature or at a higher temperature (e.g., about 60-80 ° C).

Referring to process (k), the reaction is usually carried out at an elevated temperature (e.g., 100-120 ° C) with an excess of trimethoxymethane or triethoxyethane.

Referring to method (1), suitable solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane), toluene, and/or DMF. This reaction is usually carried out at a higher temperature (for example, 100 to 120 ° C).

Referring to methods (m) and (u), suitable reducing agents include Na(OAc) ₃ BH and NaCNBH ₃ . Suitable solvents include methanol, ethanol and dichloromethane, or mixtures thereof. This reaction is usually carried out at ambient temperature.

Referring to the method (n), the leaving group X ² may be an alkylsulfonyl group or an arylsulfonyl group, such as a triflate group or an arylsulfonyloxy group or an alkylsulfonyloxy group. , such as a mesylate or tosylate group. Alternatively, X ² can be a leaving atom such as Cl or Br. The base can be, for example, an alkali metal carbonate, hydroxide or alkoxide such as cesium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, cesium hydroxide or potassium t-butoxide. Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane), toluene, DMF or DME. This reaction can usually be carried out at ambient temperature.

Referring to process (o), the base can be, for example, an alkali metal hydride or carbonate such as sodium hydride, potassium hydride, sodium carbonate, potassium carbonate or cesium carbonate. Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane), DMF or acetone.

Referring to the method (p), the leaving group L ² may be an alkylsulfonyloxy group such as a tosylate group or a mesylate group. The base can be an alkali metal carbonate or a hydrogencarbonate such as a sodium or potassium carbonate or bicarbonate. Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane) and DMF. The reaction can usually be carried out at a temperature ranging from ambient temperature to 50 °C.

Referring to method (q), suitable oxidizing agents include organic perbenzoic acids such as m-chloroperbenzoic acid. Conventional solvents include aprotic solvents such as DCM, ethers (such as tetrahydrofuran or p-dioxane) and DMF. The reaction temperature of this oxidation step is usually in the range of from -25 ° C to ambient temperature, for example between -20 ° C and 0 ° C.

Referring to the method (r), the leaving group L ³ may be an alkylsulfonyloxy group such as a tosylate group or a mesylate group. Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane) and DMF.

Referring to process (s), suitable bases include alkali metal carbonates or alkoxides such as cesium carbonate or sodium tributoxide. Conventional solvents include aprotic solvents such as ethers (e.g., tetrahydrofuran or p-dioxane) and DMF.

Referring to method (t), for the palladium catalyst include _{Pd (PPh 3) 4, Pd} 2 (dba) 3, Pd (OAc) 2, Pd (PPh 3) 2 Cl 2 and 1,1 '- bis (diphenylphosphino A phosphinyl) ferrocene-PdCl ₂ -dichloromethane complex.

Compounds of the genus V , Va , Vb , VII , VIII , IX , X , XI , XII , XIII , XIV , XV , XVI , XVII and XVIII are also novel compounds and are provided as other aspects of the invention.

The amine group in the compound described in any of the above methods may be protected by any conventional amine protecting group, for example, as described in Greene & Wuts, ed., "Protecting Groups in Organic Synthesis", John Wiley & Sons, Inc. Examples of the amine protecting group include a mercapto group and an alkoxycarbonyl group such as a third butoxycarbonyl group (BOC) and a [2-(trimethyldecyl)ethoxy]methyl group (SEM). Likewise, the carboxy group can be protected by any of the conventional carboxy protecting groups, for example, as described in Greene & Wuts, "Protecting Groups in Organic Synthesis", John Wiley & Sons, Inc. Examples of the carboxy protecting group include a (1-6C) alkyl group such as a methyl group, an ethyl group, and a tert-butyl group. The alcohol group can be protected by any conventional alcohol protecting group, for example, as described in Greene & Wuts, "Protecting Groups in Organic Synthesis", John Wiley & Sons, Inc. Examples of the alcohol protecting group include benzyl, trityl, decyl ether, and the like.

The compounds of formula I represent novel and potent inhibitors of protein tyrosine kinases such as PDGFR, cFMS and/or cKIT and are useful for the prevention and treatment of conditions caused by the action of such kinases.

The ability of a compound of the invention to act as a PDGFR inhibitor can be demonstrated by the assay described in Examples A and/or B.

The ability of a compound of the invention to act as a cFMS inhibitor can be demonstrated by the assay described in Example C.

The ability of a compound of the invention to act as a cKIT inhibitor can be demonstrated by the assay described in Example D.

The compounds of formula I may have therapeutic value in the treatment of diseases or conditions selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, pain and burns. In one embodiment, the compound of Formula I may have therapeutic value in the treatment of a disease or condition selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, and pain.

In one embodiment, the compounds of formula I are useful in the treatment of fibrotic diseases. Examples of fibrosis include idiopathic pulmonary fibrosis (IPF), renal systemic fibrosis (NSF), cirrhosis, diabetes-induced nephropathy, cardiac fibrosis (eg, endocardial fibrosis), mediastinal fibrosis, Myelofibrosis, retroperitoneal fibrosis, Crohn's disease, keloid formation, scleroderma, and systemic sclerosis. Other examples of fibrotic diseases include focal segmental glomerulosclerosis (FSGS), systemic sclerosis with interstitial lung disease (SSc-ILD), primary biliary cirrhosis, alcoholic cirrhosis, Interstitial fibrosis and tubular atrophy (CAD), proliferative vitreoretinopathy and scars (hypertrophic scars and keloids).

In one embodiment, the compounds of formula I are useful in the treatment of bone related diseases.

Examples of bone-related diseases include metastatic bone disease, treatment-induced bone loss, osteoporosis, rheumatoid arthritis, ankylosing spondylitis, Paget's disease, and periodontal disease. Osteoporosis can be attributed to (1) menopause, (2) aging of men or women, (3) suboptimal bone growth that does not reach peak bone quality during childhood and adolescence, and/or (4) other Bone loss due to disease conditions, eating disorders, medication, and/or medical treatment (eg, caused by glucocorticosteroids, aromatase inhibition therapy, or antiandrogen therapy).

Other osteolytic diseases that can be treated in accordance with the present invention are more local. A specific example is metastatic tumor-induced osteolysis. In this condition, bone cancer or bone metastasis induces local osteolysis, causing pain, bone fragility and fracture. This local osteolysis also causes the tumor to grow larger by creating a larger space for the tumor in the bone and releasing the growth factor in the bone matrix. Cancers that are known to cause tumor-induced osteolysis include hematological malignancies (such as myeloma and lymphoma) and solid tumors (such as breast, prostate, lung, kidney, and thyroid tumors), and the present invention contemplates treating all such cancers.

In one embodiment, the compounds of formula I are useful in the treatment of cancer and proliferative disorders. Examples include multiple myeloma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, giant cell tumor of bone (also known as For osteoclasts, giant cell tumor of the tendon sheath (also known as tendon sheath synovial giant cell tumor or TGCT), tumor metastasis to other tissues, other chronic myeloproliferative diseases (such as myelofibrosis), and pigmented villonodular nodules Sexual synovitis (PVNS).

In one embodiment, the compounds of formula I are useful in the treatment of autoimmune disorders and inflammatory diseases.

Examples of autoimmune disorders and inflammatory diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, adult Still's disease, glomerulus Nephritis, osteoporosis, Sjogren's syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Langerhans cell histiocytosis, hemophagocytic syndrome, Multicentric reticular cell hyperplasia and Paget's disease. Other examples of autoimmune diseases or conditions include primary sclerosing cholangitis and graft rejection (including liver, kidney, and heart/lung grafts).

In one embodiment, the compounds of formula I are useful in the treatment of cardiovascular diseases. Examples of cardiovascular diseases include atherosclerosis, peripheral vascular disease, coronary artery disease, ischemia/reperfusion, hypertension, restenosis, pulmonary hypertension, and arterial inflammation. Other examples of cardiovascular disease include acute respiratory distress syndrome (ARDA), arteriovenous (AV) internal hemorrhoids, and venous obstruction (post-HSC/BMT).

In one embodiment, the compound of formula I is useful for treating pain. In one embodiment, the compounds of formula I are useful for treating pain caused by nerve damage. In one embodiment, the compound of Formula I is useful for treating neuropathic pain associated with neuroinflammation (neuritis) in the absence of nerve damage. These pain syndromes include back pain, temporomandibular joint (TMJ) disorders, and rheumatoid arthritis.

In one embodiment, the compound of formula I is useful for treating burns.

The compounds of formula I may be administered alone as the sole therapy or may be administered in combination with one or more other substances and/or therapies that act by the same or different mechanisms of action. The combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially or separately.

Accordingly, the present invention further provides a method of treating a bone-related disease in a mammal, including a human, by administering to the mammal in need thereof a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof. achieve. The compound can be administered alone or in combination with one or more drugs that act on the same or different mechanisms of action to treat a bone-related disease.

The invention further provides a method of treating cancer in a mammal, including a human, by administering to a mammal in need thereof a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

In the field of oncology, a combination of different forms of treatment is often used to treat each meta cancer patient. In the oncology department, other components of the combination therapy other than the composition of the invention may be, for example, surgery, radiation therapy, chemotherapy, signal transduction inhibitors, and/or monoclonal antibodies.

Thus, a compound of formula I can be administered in combination with one or more agents selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, insertional antibiotics, growth factor inhibitors, signals Transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, cytostatics Antiandrogens, targeted delivery antibodies, HMG-CoA reductase inhibitors, and isoprenyl protein transferase inhibitors.

The invention also provides a method of treating a cardiovascular disease in a mammal, including a human, by administering to a mammal in need thereof at least one compound of formula I or a pharmaceutically acceptable salt thereof. The compounds can be administered alone or in combination with one or more drugs that act on the same or different mechanisms of action to treat cardiovascular disease.

The invention also provides a method of treating an inflammatory disease in a mammal, including a human, by administering at least one compound of formula I or a pharmaceutically acceptable salt thereof. The compounds can be administered alone to treat an inflammatory disease, or can be administered in combination with one or more drugs that act on the same or different mechanisms of action to treat an inflammatory disease, such as a gold salt or methotrexate.

The invention also provides a method of treating pain in a mammal, including a human, by administering to a mammal in need thereof at least one compound of formula I or a pharmaceutically acceptable salt thereof. The compounds can be administered alone to treat pain, or can be administered in combination with one or more drugs that act on the same or different mechanisms of action to treat pain.

The invention also provides a method of treating a burn in a mammal, including a human, by administering to a mammal in need thereof at least one compound of formula I or a pharmaceutically acceptable salt thereof.

The term "treating" as used herein refers to a complete or partial reduction associated with a condition or condition (eg, a bone-related disease, fibrosis, cancer, autoimmune disorder, inflammatory disease, cardiovascular disease, or pain as described herein). Symptoms, or slow or stop further progression or worsening of these symptoms.

In one embodiment, the compound of Formula I is useful for preventing a disease or condition selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, and pain in a mammal.

The term "prevention" as used herein refers to the complete or partial prevention of a disease or condition (eg, a bone-related disease, fibrosis, cancer, autoimmune disorder, inflammatory disease, cardiovascular disease, or pain as described herein) or Symptoms, recurrence or spread.

The phrase "effective amount" as used herein refers to (i) treating or preventing a particular disease, condition or disorder when administered to a mammal in need of such treatment; (ii) reducing, ameliorating or eliminating the particular disease, disease One or more symptoms of a condition or disorder, or (iii) an amount of a compound that prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

The amount of the compound of formula I corresponding to this amount will depend on a number of factors, such as the particular compound, the condition and severity thereof, and the characteristics (e.g., weight) of the mammal in need of treatment, but nevertheless may be understood by those skilled in the art. Determined according to the routine.

The term "mammal" as used herein refers to a warm-blooded animal suffering from or at risk of developing the disease described herein, and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and Primates, including humans.

The compounds of the invention may be administered by any conventional route, for example, into the gastrointestinal tract (e.g., transrectally or orally), nasal, pulmonary, musculature or vasculature or transdermally or dermally. The compound to be administered may be in any conventional pharmaceutical form such as a tablet, a powder, a capsule, a solution, a dispersion, a suspension, a syrup, a spray, a suppository, a gel, an emulsion, a patch, and the like. Such compositions may contain components commonly used in pharmaceutical preparations such as diluents, carriers, pH adjusting agents, sweetening agents, bulking agents, and other active agents. If parenteral administration is desired, the compositions should be sterile and in the form of a solution or suspension suitable for injection or infusion. These compositions form another aspect of the invention.

The invention further provides a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises a compound of formula I and a pharmaceutically acceptable diluent or carrier.

The invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in therapy. In one embodiment, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a mammal selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, A disease or condition of cardiovascular disease and pain. In one embodiment, the disease is fibrosis. In one embodiment, the disease is a bone related disease. In one embodiment, the disease is cancer. In one embodiment, the disease is an autoimmune disorder. In one embodiment, the disease is an inflammatory disease. In one embodiment, the disease is a cardiovascular disease. In one embodiment, the condition is pain. In one embodiment, the condition is a burn.

According to another aspect, the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of a mammal selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory A disease or condition of disease, cardiovascular disease, and pain. In one embodiment, the disease is fibrosis. In one embodiment, the disease is a bone related disease. In one embodiment, the disease is cancer. In one embodiment, the disease is an autoimmune disorder. In one embodiment, the disease is an inflammatory disease. In one embodiment, the disease is a cardiovascular disease. In one embodiment, the condition is pain. In one embodiment, the condition is a burn.

According to another aspect, the invention provides the use of a compound of formula I for the manufacture of a mammal for treatment selected from the group consisting of fibrosis, bone related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases and pain A medicament for a disease or condition, the treatment comprising administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the disease is fibrosis. In one embodiment, the disease is a bone related disease. In one embodiment, the disease is cancer. In one embodiment, the disease is an autoimmune disorder. In one embodiment, the disease is an inflammatory disease. In one embodiment, the disease is a cardiovascular disease. In one embodiment, the condition is pain. In one embodiment, the condition is a burn.

Instance

The following examples illustrate the invention. In the examples below, all temperatures are expressed in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, Alfa, Aesar, TCI, Maybridge or other suitable suppliers and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF), dichloromethane (DCM), toluene, dimethylformamide (DMF) and dioxane were purchased from DriSolve or other commercial vendors and used as received.

The reactions described below are generally carried out under normal nitrogen or argon pressure or by means of a drying tube (unless otherwise stated) in an anhydrous solvent, and the reaction flask is usually equipped with a rubber septum to introduce the matrix and reagents by means of a syringe. The glassware is dried by oven drying and/or heat, or dried under a stream of dry nitrogen.

Column chromatography is performed on a Biotage system (manufacturer: Dyax Corporation) with a silicone or C-18 reverse phase column or on a cerium oxide SepPak filter (Waters), or a conventional flash tube is used on the silicone. Column chromatography was carried out.

The abbreviations used in this article have the following meanings:

Example A

Phosphorylated PDGFR cell assay

Compounds that inhibit PDGFR beta phosphorylation are screened in cell lines of HS27 human fibroblasts. The cells were seeded in 96-well tissue culture plates and subsequently cultured overnight at 37 ° C in a 5% CO ₂ incubator. The next day, the cells were treated with a dilution of the test compound for 1 hour. After 5 minutes of stimulation with PDGF-BB ligand, cells were lysed and added to a sandwich ELISA plate of the R&D system to detect the extent of phosphorylated PDGFR beta. The standard 4-parameter logistic model (4-parameter logistic model) with the dose response curve fit inhibitor, IC ₅₀ is defined as the concentration which caused 50% control (POC) of the inhibitor.

Instance B

Phosphorylation of PDGFR LICOR Cell Assay

Compounds that inhibit PDGFR beta phosphorylation are screened in cell lines of HS27 human fibroblasts. The cells were seeded in 96-well tissue culture plates and subsequently cultured overnight in a 37 ° C / 5% CO ₂ incubator. The next day, the cells were treated with a dilution of the test compound for 1 hour. After stimulation with PDGF-BB ligand for 10 minutes, the cells were washed with PBS and fixed in PBS containing 3.7% formaldehyde for 10 minutes. It was then washed in PBS/0.2% Triton X-100 and permeated in 100% MeOH for 10 minutes. The cells were cultured for 1 hour in blocking buffer. The antibody against phosphorylated PDGFRβ and total ERK were added to the cells and cultured for 3 hours. After washing with PBS/0.2% Triton X-100, the cells were incubated with the fluorescently labeled secondary antibody for an additional hour. The cells were then washed with PBS and analyzed for fluorescence at both wavelengths using an Odyssey Infrared Imaging System (LI-COR Biosciences). The phosphorylated PDGFR signal was normalized to the total ERK signal. The standard 4-parameter logistic model with the inhibitor dose-response curve fitting, wherein IC ₅₀ is defined as the concentration causing 50% control (POC) of the inhibitor.

Example C

Cell-based cFMS assay

The ability of a compound of formula I to inhibit cFMS activation in a cell is determined by the following assay. THP-1 cells (human acute monocytic leukemia cell line) were serum starved for 4 hours and then treated with the compound of formula I for 1 hour. The concentration of the compound of formula I varies between 9 and 3 fold serial dilutions, with 5,000 nM being the highest dose. Cell culture and treatment were carried out in a humidified 37 ° C, 5% CO ₂ incubator. Treated cells were stimulated with 250 ng/mL recombinant human MCSF for 1 minute to induce cFMS activation. The cells were lysed by retaining the phosphorylated protein, and the lysate was analyzed by ELISA (R&D Systems, Human Phospho-M-CSF R DuoSet IC DYC3268), in which all cFMS proteins in the lysate were captured, and the phosphoric acid of cFMS was detected. A tyrosine residue. A standard curve prepared using purified phosphoric acid M-CSF R protein was used to quantify phosphorylated c-FMS in compound treated wells. The standard 4-parameter logistic model with the inhibitor dose-response curve fitting, wherein IC ₅₀ is defined as the concentration causing 50% control (POC) of the inhibitor.

Example D

Cell-based c-KIT assay

The ability of a compound of formula I to inhibit c-KIT activation in a cell is determined by the following assay. M-07e cells (human acute megakaryoblastic leukemia cell line) were serum starved for 4 hours and then treated with the compound of formula I for 1 hour. The concentration of the compound of formula I varies between 9 and 3 fold serial dilutions, with 5,000 nM being the highest dose. Cell culture and treatment were carried out in a humidified 37 ° C, 5% CO ₂ incubator. The treated cells were stimulated with 150 ng/ml recombinant human SCF for 4 minutes to induce c-KIT activation. The cells were lysed by retaining the phosphorylated protein, and the lysate was analyzed by ELISA (R&D Systems, Human Phospho-M-CSF R DuoSet IC DYC3268), in which all c-KIT proteins in the lysate were captured, and c was detected. -Kit's phosphotyrosine residue. A standard curve prepared using purified phosphoric acid SCFR protein was used to quantify phosphorylated c-KIT in compound treated wells. The standard 4-parameter logistic model with the inhibitor dose-response curve fitting, wherein IC ₅₀ is defined as the concentration causing 50% control (POC) of the inhibitor.

In Table A provides examples A, B, C and / or D the average assay IC ₅₀ values of test compounds of Formula I.

Preparation of synthetic intermediates

Preparation A

7-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid Ethyl ester

Step A: Preparation of 4-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-2-amine: sodium hydride (60% in mineral oil; 43.56 g; 1089) Methyl) was added to a 3 L reaction flask. A mechanical stirrer and thermocouple are attached. Anhydrous diglyme (400 mL) was added. A solution of 2-(4-methylpiperazin-1-yl)ethanol (157 g; 1089 mmol) in diglyme (450 mL) was slowly added with stirring. The mixture was stirred while warming to 40 ° C for 1 hour. Solid 4-chloropyridin-2-amine (70.0 g; 544.5 mmol) was added. The mixture was heated to 80 ° C with stirring until the foaming was stopped. The temperature was increased to 157 ° C for 16 hours. The mixture was allowed to cool and diluted with water (500 mL). THF (1000 mL) and sodium chloride (sufficient to saturate the aqueous phase) were added sequentially. The phases were separated and the aqueous phase was further extracted with THF (3×800 mL). Add water if necessary to help phase separation. The combined organic phases were dried over sodium sulphate (1000 g) and filtered. The solvent was removed under vacuum to remove most of the THF. The solution was filtered through Celite to remove fine particles and rinsed with diglyme. Diethylene glycol dimethyl ether was removed under vacuum (10 mm Hg vacuum while the bath temperature was increased to 60 °C). The residue was placed under high vacuum for 1 hour and then was tribr. dried with diethyl ether (400 mL). The resulting solid was taken from EtOAc (EtOAc)EtOAc.

Step B: Preparation of 4-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-2-amine: 2-chloro-3-ethoxy-3-oxo-propan-1 Potassium eno-1-carboxylate (120 g, 635 mmol) was suspended (via vigorous magnetic stirring) in 1800 mL of diethyl ether and 6 N sulfuric acid (53 mL, 317 mmol) was slowly added. The lower aqueous suspension was periodically sampled to determine the acidity. Additional water (100 mL) was added to aid in phase separation. When the pH of the lower (water) phase drops below 3, the ether phase is separated. The aqueous phase was extracted again with diethyl ether (200 mL). The combined ether phases were dried over sodium sulfate and magnesium sulfate for 10 min. The solution was filtered and concentrated under reduced pressure while the temperature did not exceed 20 °C. Obtained as an off-white semi-solid (100 g). This semi-solid was dissolved in absolute ethanol (800 mL). 4-(2-(4-Methylpiperazin-1-yl)ethoxy)pyridin-2-amine (Preparation C; 75 g, 317 mmol) was added and the mixture was heated at 65 ° C for 18 hours under nitrogen. . The mixture was cooled to ambient temperature and the resulting suspension was evaporated to dryness. The resulting solid was triturated with THF, collected by filtration and then dried in vacuo. This material (hydrochloride) was mixed with water (1 L) and ethanol (500 mL). Sodium bicarbonate (50 g) was added and the mixture was stirred for 18 hours. The suspension was evaporated to dryness under vacuum. The solid was extracted with a larger volume of ethyl acetate (4 L) and THF (1 L). The organic solution was further dried with sodium sulfate and MgSO. The material was triturated with EtOAc (EtOAc)EtOAc.

Preparation B

(E)-2-Chloro-3-ethoxy-3-oxooxyprop-1-en-1-phosphate

A mixture of ethyl 2-chloroacetate (220.8 g; 1802 mmol) and ethyl formate (133.5 g; 1802 mmol) was slowly added to potassium t-butoxide (202.2 g; 1802 mmol). ) in a suspension in diisopropyl ether (2000 mL) (maintaining temperature < 20 ° C). The mixture was stirred at ambient temperature for 24 hours. The solid was collected by filtration and washed with diisopropyl ether (500 mL) and acetonitrile (2×1500 mL). The material was dried <RTI ID=0.0></RTI> to <RTI ID=0.0>

Preparation C

Ethyl 6-isopropylpyridinecarboxylate

Step A: Preparation of tert-butyl 4-fluoropyridin-2-ylaminocarbamate : Under a dry nitrogen atmosphere, the flask was charged with 2-chloro-4-fluoropyridine (20 g, 152 mmol), carbamic acid. Third butyl ester (89 g, 760 mmol), ginseng (dibenzylideneacetone) dipalladium (1.39 g, 1.52 mmol), X-PHOS (1.48 g, 3.10 mmol), cesium carbonate (99 g, 588 mmol) And tetrahydrofuran (500 mL). The mixture was heated under reflux for 7 hours under nitrogen. An additional 1 equivalent of cesium carbonate was added and the reaction was further heated for 7 hours. The mixture was cooled to ambient temperature, filtered through EtOAc (EtOAc)EtOAc. The filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organics were washed with EtOAc EtOAc EtOAc m.

Step B: Preparation of 4-fluoropyridin-2-amine : The flask was charged with tert-butyl 4-fluoropyridin-2-ylcarbamate (3.5 g, 16.5 mmol) and dichloromethane (100 mL). The mixture was cooled to 0-5 ° C using an ice/water bath. Trifluoroacetic acid (75 mL) was added slowly with constant stirring. The mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo then partitioned between sat. The aqueous layer was washed twice with ethyl acetate. The combined organics were washed with EtOAc EtOAc m.

Step C: Preparation of ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate : 4-fluoropyridin-2-amine (10.0 g, 48.0 mmol) and ethanol (40) under dry nitrogen atmosphere mL) was mixed in the reaction flask. A solution of ethyl 2-chloro-3-oxopropionate (5% benzene solution, 178 mL (a solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60 ° C under nitrogen for 4 hours. The mixture was allowed to cool and the solvent was evaporated in vacuo to afford a brown solid. EtOAc EtOAc (EtOAc) The bicarbonate solution was extracted with an ester (75 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a solid. Ethyl acetate was dissolved. The fractions containing the desired material were crystallised to afford ethyl <RTIgt;</RTI><RTIgt;</RTI><RTIgt;

Step D: Preparation of ethyl 6-chloropicolinate : A flask equipped with a condenser was charged with 6-chloropicolinic acid (23.5 g, 149 mmol), 100 mL of ethanol and 400 mL of toluene. 4 mL of sulfuric acid was added thereto and the mixture was allowed to warm to reflux for 3 hours and then cooled to ambient. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ .

Step E: Preparation of ethyl 6-(prop-1-en-2-yl)pyridinecarboxylate: The first flask was charged with 1,4-dioxane/H ₂ O (50 mL / 10 mL). The flask was cooled to 0 ° C and a vacuum was applied for 20 min. The second flask was charged with ethyl 6-chloropicolinate (4.200 g, 22.63 mmol), potassium trifluoro(prop-1-en-2-yl)borate (4.353 g, 29.42 mmol), potassium carbonate (4.378 g). , 31.68 mmol), diethyl p-methoxy palladium (0.1524 g, 0.6789 mmol) and sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.6959 g, 1.358 mmol). The second flask was also evacuated by vacuum and backfilled N ₂ 3 times. Degassed cold dioxane/H ₂ O was then added to the second flask, evacuated with vacuum and backfilled with argon 5 times. The reaction mixture was heated to 80 ° C for 3 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was then diluted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO _3, dried (Na ₂ SO ₄₎ and concentrated to give quantitative yield of the 6- (prop-1-en-2-yl) pyridine carboxylic acid ethyl ester, which was used without further purification In the next step.

Step F: Preparation of ethyl 6-isopropylpicolinate: added to ethyl 6-(prop-1-en-2-yl)pyridinecarboxylate (4.63 g, 24.2 mmol) dissolved in EtOH (50 mL) Pd/C (0.61 g, 0.573 mmol). The reaction mixture was purged with nitrogen three times and then purged three times with hydrogen. A hydrogen balloon was applied to the reaction for 3 hours. The reaction was then washed with N ₂ blowing, filtered through diatomaceous earth and washed with EtOH (100 mL). The solvent was removed under reduced pressure to give 4.36 g (yield: 93%)

Preparation D

1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine

Step A: Preparation of (6-isopropylpyridin-2-yl)methanol) : Ethyl 6-isopropylpyridinecarboxylate (prepared as prepared in Preparation C: 75 g, 0.39 mol) was dissolved in 1.5 liters of anhydrous THF. Cool to 0 ° C and slowly add lithium aluminum hydride (0.39 L, 0.39 mol, 1 M in THF) over 20 min. The resulting dark solution was stirred at 0 °C for 30 minutes and then allowed to warm to ambient temperature. TLC showed complete consumption of the starting material. The reaction mixture was cooled to 0 ° C and was carefully quenched by the addition of sodium sulfate dehydrate until gas evolution was not observed. A thick mixture is obtained. Dioxane and diethyl ether (about 200 mL) were added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a brown oil. The filter cake was slurried overnight in IPA / EtOAc and filtered to give 8 g product (68%).

Step B: Preparation of 2-(chloromethyl)-6-isopropylpyridine hydrochloride : 6-isopropylpyridin-2-yl)methanol (40 g, 0.265 mol) was dissolved in 500 mL of anhydrous dichloromethane Medium and cooled to 0 °C. Thionium chloride (37.8 g, 0.317 mol) was added thereto and the mixture was stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure to give 2-(chloromethyl)-6-isopropylpyridine hydrochloride.

Step C: Preparation of 3-bromo-4-nitro-1H-carbazole : Add sodium acetate (26.4 g, 0.306 mol), 4-nitro-1H-carbazole (50 g) to a flask equipped with a mechanical stirrer , 0.306 mol), 300 mL of acetic acid and 300 mL of chloroform. Bromine (51.4 g, 0.322 mol) dissolved in 60 mL of acetic acid was added to the reaction mixture over 3.5 hours while maintaining the temperature below 25 °C. The reaction mixture was stirred for 2 hr then concentrated under reduced pressure. Water (500 mL) was added to the resulting solid. The solid was collected by filtration, washed with water (500 mL) and dried in vacuo to afford 68 g (92%) of 3-bromo-4-nitro-1H-carbazole.

Step D: Preparation of 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-carbazole: loading the flask with 3-bromo-4-nitro -1H-carbazole (64 g, 0.264 mol), 2-(chloromethyl)-6-isopropylpyridine hydrochloride (55 g, 0.264 mol), powdered potassium carbonate (91 g, 0.661 mol) 500 mL DMF. The mixture was allowed to warm to 35 ° C for 72 hours and then poured into 2 liters of cold water at which time a light brown solid precipitated. After stirring for 20 minutes, the solid was collected by filtration and dried in vacuo to give &lt;RTI ID=0.0&gt;&gt; 1H-carbazole.

Step E: Preparation of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole: loading dioxins into a 3 liter thick wall reaction flask Alkane (1 liter), 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (90 g, 0.24 mol), methylboronic acid ( 72 g, 1.20 mol), Pd(PPh ₃ ) ₄ (9.7 g, 0.0084 mol), potassium carbonate (99.5 g, 0.719 mol), followed by 200 mL of water. The mixture was purged with argon for 10 minutes, the flask was sealed and heated to 120 ° C for 16 hours. Then 1.5 mol% Pd(PPh ₃ ) ₄ and 2 equivalents of methylboronic acid were added sequentially, and the mixture was warmed to 120 ° C for 24 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography (5% ethyl acetate / hexanes to 10% ethyl acetate / hexanes) afforded 54 g (73%) )methyl)-3-methyl-4-nitro-1H-carbazole.

Step F: Preparation of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine : in a flask equipped with an overhead stirrer and a condenser Loading 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (25 g, 0.081 mol) and 150 mL of ethanol, followed by loading 45 g (0.805 mol) iron powder. An equal amount of saturated ammonium chloride solution was added and the mixture was brought to 80 °C. After 5 hours of heating, the mixture was allowed to cool to ambient temperature, diluted with water (500 mL) and filtered through GF/F filter paper multiple times to remove iron and iron salts. The filtrate was extracted with EtOAcaq. Column chromatography (1:1 ethyl acetate/hexane to 100% ethyl acetate) afforded 12.6 g (56%) of 1-((6-isopropylpyridin-2-yl)methyl)-3- Methyl-1H-indazole-4-amine.

Instance

Example 1

N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(N-morpholinyl) Oxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2 -a]pyridine-3-carbamide : 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine (Preparation D; 0.673 g , 2.40 mmol) and ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (Step C, 0.500 g, 2.40 mmol) were dissolved in anhydrous THF (24 mL) and cooled to 0. LiHMDS (5.28 mL, 5.28 mmol, 1 M in THF) was added over a 5 min period by syringe. Once the addition is complete, the reaction mixture is removed from the cooling bath and allowed to warm to ambient temperature. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with aq. The crude material was purified by column chromatography (100% ethyl acetate) to afford 775 mg (73%) of 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl) 3-Methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide.

Step B: Preparation of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(N-? Phenyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : 7-fluoro-N-(1-((6-isopropylpyridine-2-) in a reaction tube Methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.250 g, 0.565 mmol), 2-(N-? Alkyl)ethanol (0.371 g, 2.82 mmol) and potassium t-butoxide were combined in t-BuOH. The tube was sealed and heated to 95 ° C for 16 hours. After cooling to ambient temperature the mixture was diluted with water and EtOAc. The combined organic extracts were dried with sodium s The obtained crude product was triturated with diethyl ether to give 165 mg (53%) of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-carbazole as a light brown solid. 4-yl)-7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide. MS (APCI), positron emission scan, m/z = 554.1 (M+H).

real Example 2

7-(2-(4-Ethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H -oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(4-ethylpiperazin-1-yl)ethanol: 1-ethylpiperazine (5.0 g, 43.8 mmol) was dissolved in 90 mL of acetonitrile followed by powdered potassium carbonate (18.2 g) , 131 mmol) and 2-bromoethanol (10.9 g, 87.6 mmol). The mixture was allowed to warm to reflux for 16 h, cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (10% MeOH / DCM / 0.5 % NH 4 OH), to give 5.4 g (78%) as a pale yellow oil of 2- (4-ethyl-piperazine -1 -Base) Ethanol.

Step B: Preparation of 7-(2-(4-ethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3- Methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide: Prepared as described in Step B of Example 1, using 2-(4-ethylpiperazine- 1-(N-M-morpholinyl)ethanol was replaced by 1-ethyl)ethanol to give the title compound (22%). MS (APCI), positron emission scan, m/z = 581.1 (M+H).

Example 3

7-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)- 3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride

Step A: Preparation of 3-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2- carboxylic acid tert- butyl ester: Prepared as described in Example 2, Step A, using 2, Substituting 1-ethylpiperazine for the 6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxalate gave the title compound (36%).

Step B: Preparation of 6-(2-(3-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-ylaminemethyl) Imidazo[1,2-a]pyridin-7-yloxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester : as in Example 1, Step B Prepared by substituting 2-(N-morpholinyl)ethanol with 6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester to give 0.8. g (33%) of the title compound.

Step C: Preparation of 7-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)) Methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride: 6-(2-(3-(1) -((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-ylaminemethanyl)imidazo[1,2-a]pyridin-7-yl Oxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.075 g, 0.113 mmol) was dissolved in 2 mL of 1:1 DCM/MeOH and added 4 M HCl / dioxane (0.282 mL, 1.13 mmol). The mixture was stirred at ambient temperature for 4 hours and then concentrated under reduced pressure. The resulting residue was triturated with EtOAc EtOAc (EtOAc) MS (APCI), positron emission scan, m/z = 567.1 (M+H).

Example 4

N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2, 6-diazaspiro[3.3]hept-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanol : 6-(2-hydroxyethyl)-2,6-diazaspiro [3.3] H-butane-2-carboxylic acid tert-butyl ester (0.620 g, 2.56 mmol) was dissolved in dry THF (13 mL) and cooled to EtOAc. Lithium aluminum hydride (7.68 mL, 7.68 mmol, 1 M in THF) was added by syringe. Once the addition was complete, the mixture was allowed to reach reflux for 16 hours. The reaction was cooled to 0 ° C, quenched with 291 μL of water, 291 μL of 15% aqueous NaOH and 873 μL of water, and stirred vigorously for 2 s and then filtered. The filtrate was concentrated under reduced pressure to give 268 mg (67%

Step B: Preparation of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-A) Base-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : prepared as described in Example 1, Step B Substituting 2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanol for 2-(N-morpholinyl)ethanol gave the title compound (20%). MS (APCI), positron emission, m/z = 580.6, 581.7 (M+H).

Example 5

7-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl) )-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanol : Prepared as described in Step 2, Example 2, using 2-oxa-6-aza snail [3.3] Heptane oxalate was substituted for 1-ethylpiperazine to give the title compound (17%).

Step B: Preparation of 7-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy)-N-(1-((6-isopropylpyridine-2-) Methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : Prepared as described in Step B of Example 1, using 2 Substituting 2-(N-morpholinyl)ethanol with 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethanol gave the title compound (50%). MS (APCI), positron emission scan, m/z = 566.1 (M+H).

Example 6

7-(2-(4-Isopropylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl- 1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared as described in Example 1 Step B, substituting 2-(4-isopropylpiperazin-1-yl)ethanol in 2-(N-morpholinyl)ethanol to give the title compound (55%). MS (APCI), positron emission scan, m/z = 595.2 (M+H).

Example 7

N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((3S,5R)-3) ,4,5-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a] Pyridine-3-carboxamide

Step A: Preparation of (3R,5S)-3,4,5-trimethylpiperazine-1-carboxylic acid tert-butyl ester : (3R,5S)-3,5-dimethylpiperazine-1-carboxylic acid The third butyl ester (1.50 g, 7.00 mmol) was dissolved in 70 mL of methanol. 37% aqueous formaldehyde solution (1.17 mL, 14.0 mmol) and formic acid (1.14 mL, 24.5 mmol) were added. The reaction mixture was heated to 70 ° C for 24 hours then concentrated under reduced pressure. The resulting oil was taken from EtOAc EtOAc.

Step B: Preparation of (2S,6R)-1,2,6-trimethylpiperazine dihydrochloride : (3R,5S)-3,4,5-trimethylpiperazine-1-carboxylic acid third Butyl ester (1.17 g, 5.12 mmol) was dissolved in 50 mL EtOAc and cooled to EtOAc. HCl gas was bubbled through the solution for 20 minutes, and then the reaction flask was firmly capped and the mixture was stirred at ambient temperature for 16 hours. Excess HCl gas was purged from the mixture with a steady stream of nitrogen and the mixture was concentrated under reduced pressure to yield 1 g (97%)

Step C: Preparation of 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol : Prepared according to Step 2 of Example 2, using (2S, 6R) -1, 2, Substituting 1-ethylpiperazine with 6-trimethylpiperazine dihydrochloride gave 0.856 g (100%) of the title compound.

Step D: Preparation of ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate : Add 2-chloro-3-ethoxyl to a flask equipped with a reflux condenser, mechanical stirring and internal temperature probe Potassium 3-oxopropan-1-en-1-nate (58.70 g, 311.1 mmol) was subsequently charged with 200 mL of EtOH. An aqueous solution of hydrogen chloride (4.862 ml, 15.56 mmol) dissolved in EtOH was added to the slurry. The slurry was stirred for about 15 minutes, and then 4-chloropyridin-2-amine (20.00 g, 155.6 mmol) was added and the mixture was warmed to 70 °C. After about 1 hour, another 2 equivalents of a 3.2 M aqueous hydrochloric acid solution was added and the mixture was stirred at 70 ° C for 16 hours. Further, 30 g of potassium 2-chloro-3-ethoxy-3-oxopropan-1-en-1-nate was added and the mixture was stirred at 70 ° C for 2 hours. The mixture was cooled to ambient temperature and 500 mL of water was added, then the pH was adjusted to 11 with 10% aqueous sodium carbonate. After stirring for several hours, the solid which precipitated was collected by filtration and dried in vacuo to give 31 g (88%)

Step E: Preparation of 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2 -a]pyridine-3-carboxamide : Prepared according to step A of Example 1, substituting 7-fluoroimidazo[1,2- with ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate a] Pyridine-3-carboxylic acid ethyl ester gave the title compound (56%).

Step F: Preparation of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((3S, 5R)-3,4,5-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : loading 7-chloro- into the pressure tube N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-methyl Indoleamine (0.500 g, 1.09 mmol), 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol (0.375 g, 2.18 mmol), dissolved in 10 mL DMSO Crushed potassium hydroxide (0.306 g, 5.45 mmol). The tube was sealed and heated to 95 ° C for 16 hours and then allowed to cool to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine w... Column chromatography (10% MeOH / DCM / 0.5% NH ₄ OH) followed by tribr. MS (APCI), positron emission scan, m/z = 595.1 (M+H).

Example 8

N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2 -(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 1-isopropyl-5-methyl-1H-pyrazole-3-carboxylate : 2,4-dioxy valeric acid dissolved in acetic acid (100 mL) at 0 °C Isopropyl hydrazine (9.42 g, 127 mmol) was added dropwise to ethyl acetate (20.1 g, 127 mmol). The cooling bath was removed and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with EtOAc / H ₂ O (300 mL / 100 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (100 mL), washed with H ₂ O (50 mL) and brine (50 mL). The organic layer was dried (Na ₂ SO ₄₎ and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc

Step B: Preparation of (1-isopropyl-5-methyl-1H-pyrazol-3-yl)methanol : 1-isopropyl-5-A in THF (50 mL) at 0 ° Ethyl-1H-pyrazole-3-carboxylate (7.68 g, 39.1 mmol) was added LAH (1.49 g, 39.1 mmol). The cooling bath was removed and the reaction mixture was stirred for 2 hours and then carefully quenched with sodium sulfate decahydrate. The reaction mixture was filtered through diatomaceous earth and washed with Et ₂ O. The filtrate was concentrated under reduced pressure to give 5.3 g (yel.

Step C: Preparation of 3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazole hydrochloride : Prepared according to Preparation D Step B using (1-isopropyl-5-- Substituting isopropyl-1H-pyrazol-3-yl)methanol to isopropylpyridin-2-yl)methanol afforded 7.1 g (99%) of the title compound.

Step D: Preparation of 3-bromo-1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-carbazole : according to Preparation D step Preparation of D, replacing 2-(chloromethyl)-6-isopropylpyridine hydrochloride with 3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazole hydrochloride, 9.12 g (71%) of the title compound are obtained.

Step E: Preparation of 1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-4-nitro-1H-carbazole : into a flask Load 1,4-dioxane/H ₂ O (30 mL/5 mL). The flask was cooled to 0 ° C and vacuum was applied for 20 minutes. The second flask was charged with 3-bromo-1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-carbazole (1.95 g, 5.16 mmol), K ₂ CO ₃ (2.85 g, 20.6 mmol), diethoxyphosphonium palladium (0.0579 g, 0.258 mmol), methylboronic acid (0.926 g, 15.5 mmol) and 2'-(dicyclohexyl) Sodium phosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.264 g, 0.516 mmol). The second flask was evacuated and backfilled with nitrogen 3 times. Degassed cold dioxane/H ₂ O was added to the second flask, evacuated and backfilled with argon 5 times. The reaction mixture was heated to 80 ° C for 3 hours. The reaction was cooled to ambient temperature and filtered and concentrated EtOAc. The residue was diluted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO ₃ (30 mL), dried (Na ₂ SO ₄₎ and concentrated to give 1.34 g (83%) of the title compound, which was used without further purification in the next step.

Step F: Preparation of 1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazole-4-amine : according to Preparation D Prepared by F, replacing 1- with 1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-4-nitro-1H-carbazole ((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole gave 0.86 g (72%)

Step G: Preparation of 7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazole-4 -yl)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step A of Example 1, using 1-((1-isopropyl-5-methyl-1H-pyrazole-3) -yl)methyl)-3-methyl-1H-indazole-4-amine substituted 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole- 4-Amine gave 0.245 g (60%).

Step H: Preparation of N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)- 7-(2-(6-Methyl-2,6-diazaspiro[3.3]hept-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : according to Example 1 Step B was carried out using 7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H- Oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)- 3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(6-methyl-2,6-diazaspiro[3.3] Substitution of hept-2-yl)ethanol to 2-(N-morpholinyl)ethanol gave 23 mg (25%) of the title compound. MS (APCI), positron emission scan, m/z = 583.3 (M+H).

Example 9

N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2 -((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using 7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H -oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 8, Step AG) in place of 7-fluoro-N-(1-((6-isopropylpyridine)- 2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-((3R,5S)-3 Substituting 2,5-trimethylpiperazin-1-yl)ethanol for 2-(N-morpholinyl)ethanol gave 11 mg (6%) of the title compound. MS (APCI), positron emission scan, m/z = 598.2 (M+H).

Example 10

N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2 -(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using 7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H -oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 8, Step AG) in place of 7-fluoro-N-(1-((6-isopropylpyridine)- 2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-isopropylpiperazine) Substituting 1-(N-morpholinyl)ethanol with 1-ethyl)ethanol gave 15 mg (11%) of the title compound. MS (APCI), positron emission scan, m/z = 598.1 (M+H).

Example 11

N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2 -(4-methyl-1,4-diazepan-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(2-hydroxyethyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester : Prepared according to Example 2, Step A, using 1,4-diazacyclohexane Substituting the heptane-l-carboxylic acid tert-butyl ester to 1-ethylpiperazine gave 0.845 g (46%) of the title compound.

Step B: Preparation of 2-(4-methyl-1,4-diazepan-1-yl)ethanol : Prepared according to Example 4 Step A using 4-(2-hydroxyethyl)-1, Tert-butyl 4-diazepane-1-carboxylic acid substituted with tert-butyl 6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 0.220 g (40%) of the title compound.

Step C: Preparation of N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)- 7-(2-(4-Methyl-1,4-diazepan-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : according to Example 1 Step B was carried out using 7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-carbazole -4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 8, Step AG) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl) )methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-methyl-1,4-di Substituting 2-(N-morpholinyl)ethanol with azepan-1-yl)ethanol gave 18 mg (11%) of the title compound. MS (APCI), positron emission scan, m/z = 584.1 (M+H).

Example 12

N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(chloromethyl)-2-isopropylthiazole hydrochloride: Prepared according to Preparation D Step B, substituting (2-isopropylthiazol-4-yl)methanol to isopropylpyridine- 2-Methyl)methanol gave (81%) of title compound (81%).

Step B: Preparation of 4-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-2-isopropylthiazole: Prepared according to Preparation D Step D using 4-(chloro Substituting 2-(chloromethyl)-6-isopropylpyridine hydrochloride with methyl)-2-isopropylthiazole hydrochloride gave the final product (78%).

Step C: Preparation of 2-isopropyl-4-((3-methyl-4-nitro-1H-indazol-1-yl)methyl)thiazole: Prepared according to Preparation D Step E with 4-( (3-Bromo-4-nitro-1H-indazol-1-yl)methyl)-2-isopropylthiazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl)methyl 4-Nitro-1H-carbazole gave the title compound (79%).

Step D: Preparation of 1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazole-4-amine : Prepared according to Preparation D Step F with 2-isopropyl Substituted 4-((3-methyl-4-nitro-1H-indazol-1-yl)methyl)thiazole for 1-((6-isopropylpyridin-2-yl)methyl)-3 Methyl-4-nitro-1H-indazole gave the title compound (76%).

Step E: Preparation of 7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2 -a]pyridine-3-carbamide : Prepared according to Step A of Example 1 using 1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazole-4 -Amine-substituted 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (53%).

Step F: Preparation of N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-A) Isopiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using 7-fluoro-N-(1-((2) -Isopropylthiazole-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 12, Step AE Substituting 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a Pyridine-3-carboxamide and 2-(4-methyl-1,4-diazepan-1-yl)ethanol were substituted for 2-(N-morpholinyl)ethanol to give the title compound ( 78%). MS (APCI), positron emission scan, m/z = 573.1 (M+H).

Example 13

N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2, 6-diazaspiro[3.3]hept-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using 7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carboxamide (Example 12, Step AE) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3 -methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(6-methyl-2,6-diazaspiro[3.3] Hept-2-yl)ethanol (Example 4) was substituted for 2-(N-morpholinyl)ethanol to give the title compound (41%). MS (APCI), positron emission scan, m/z = 585.1 (M+H).

Example 14

7-(2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl) )-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using 7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carboxamide (Example 12, Step AE) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3 -methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(2-oxa-6-azaspiro[3.3]hept-6 Substituting ethanol (Example 5) for 2-(N-morpholinyl)ethanol gave the title compound (53%). MS (APCI), positron emission scan, m/z = 572.0 (M+H).

Example 15

7-(2-(4-Isopropylpiperazin-1-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl- 1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using 7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carboxamide (Example 12, Step AE) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3 -Methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-isopropylpiperazin-1-yl)ethanol in place of 2- (N-morpholinyl)ethanol gave the title compound (68%). MS (APCI), positron emission scan, m/z = 601.1 (M+H).

Example 16

N -(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-cyclopropylpyridinecarboxaldehyde: A flame dried flask was charged with anhydrous THF (75 mL) and cooled to -78. To this was added n-BuLi (9.90 mL, 24.7 mmol, 2.5 M in hexanes), followed by the slow addition of 2-bromo-6-cyclopropylpyridine (4.90 g, 24.7 mmol) THF (25 mL) over 15 min. ) solution. The mixture was stirred at -78 °C for 15 min and pure DMF (2.87 mL, 37.1 mmol). The mixture was stirred at -78 °C for 15 minutes, then quenched with saturated aqueous ammonium chloride (50 mL) and allowed to warm to ambient. The mixture was diluted with water, extracted with EtOAc EtOAc EtOAc.

Step B: Preparation of (6-cyclopropylpyridin-2-yl)methanol : boron was added to 6-cyclopropylpyridinecarboxaldehyde (3.5 g, 23.8 mmol) in methanol (95 mL) cooled to 0. Sodium hydride (2.70 g, 37.8 mmol). Once the addition is complete, the cooling bath is removed and the reaction mixture is allowed to warm to ambient temperature. The mixture was concentrated under reduced EtOAc. Column chromatography (100% EtOAc as solv.)

Step C: Preparation of 2-(chloromethyl)-6-cyclopropylpyridine hydrochloride : Preparation according to Preparation D Step B, substituting 6-isopropyl with (6-cyclopropylpyridin-2-yl)methanol Pyridin-2-yl)methanol gave the title compound (100%).

Step D: Preparation of 3-bromo-1-((6-cyclopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole : Prepared according to Preparation D Step D using 2-(chloro Substitution of 2-(chloromethyl)-6-isopropylpyridine hydrochloride with methyl)-6-cyclopropylpyridine hydrochloride gave the final product (87%).

Step E: Preparation of 1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole : Prepared according to Preparation D Step E using 3-bromo 1-((6-cyclopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (Example 16, Step AD) substituted 3-bromo-1-((6-isopropyl) Pyridin-2-yl)methyl)-4-nitro-1H-indazole gave the title compound (70%).

Step F: Preparation of 1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine : Prepared according to Preparation D Step F using 1-(( 6-Cyclopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole substituted 1-((6-isopropylpyridin-2-yl)methyl)-3 Methyl-4-nitro-1H-carbazole gave the title compound (70%).

Step G: Preparation of N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2 -a]pyridine-3-carboxamide : Prepared according to step 1 of Example 1 using 1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4 -Amine-substituted 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (83%).

Step H: Preparation of N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-) Propyl piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Example 1 Step B using N-(1-((6-cyclopropyl) Pyridyl-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide substituted 7-fluoro- N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-methyl The title compound (48%) was obtained from the title compound (yield: EtOAc). MS (APCI), positron emission scan, m/z = 593.8 (M+H).

Example 17

N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-ethylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazole And [1,2-a]pyridine-3-carboxamide (Example 16, Step AG) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3 -Methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and substituting 2-(4-ethylpiperazin-1-yl)ethanol for 2-( N-morpholinyl)ethanol gave the title compound (8%). MS (APCI), positron emission scan, m/z = 579.1 (M+H).

Example 18

N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(N-morpholinyl)-ethyl Oxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazole And [1,2-a]pyridine-3-carboxamide (Example 16, Step AG) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3 -Methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide afforded the title compound (64%). MS (APCI), positron emission scan, m/z = 552.1 (M+H).

Example 19

N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7- (2-(3,3,4-Trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of tert-butyl 4-(2-hydroxyethyl)-2,2-dimethylpiperazine-1-carboxylate: Prepared as described in Step 2, Example 2, using 2,2-dimethyl Substituting 1-ethylpiperazine with a piperazine-1-carboxylic acid tert-butyl ester gave the title compound (85%).

Step B: Preparation of 2-(3,3,4-trimethylpiperazin-1-yl)ethanol: Prepared according to Example 4 Step A using 4-(2-hydroxyethyl)-2,2-dimethyl Tert-butyl 6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid was substituted with the third derivative of piperazine-1-carboxylic acid to give the title compound (100%) ).

Step C: Preparation of N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,3) , 4-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: Prepared according to Step B of Example 1, using N-(1-(( 6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide Example 16, Step AG) Substituting 7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[ 1,2-a]pyridine-3-carboxamide and 2-(3,3,4-trimethylpiperazin-1-yl)ethanol were substituted for 2-(N-morpholinyl)ethanol to give the title compound (19%). MS (APCI), positron emission scan, m/z = 593.1 (M+H).

Example 20

N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7- (2-(4-(2-methoxyethyl)piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanol : Prepared as described in Step 2, Example 2, using 2-(piperazin-1-yl)ethanol Substituting 1-ethylpiperazine gave the title compound (71%).

Step B: Preparation of N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-( 2-methoxyethyl)piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using N-(1- ((6-Cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidine Amine (Example 16, Step AG) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carboxamide and 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanol to replace 2-(N-morpholinyl)ethanol The title compound (41%) was obtained. MS (APCI), positron emission scan, m/z = 609.1 (M+H).

Example 21

N-(3-Chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazine)- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-chloro-4-nitro-1H-carbazole: To a solution of sodium hydroxide (2.94 g, 73.6 mmol) in 100 mL of water was added 4-nitro-1H-carbazole (3.00 g, 18.39 mmol) followed by sodium hypochlorite (33.4 g, 6.15% in water). The mixture was stirred overnight at ambient temperature. The mixture was acidified to pH 2 with 10% aqueous HCl and extracted with 25% IPA / DCM. The combined organic extracts were washed with water, dried over sodium sulfate The resulting solid was triturated with diethyl ether to give 1.5 g (41%

Step B: Preparation of 3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole: Prepared according to Preparation D Step D using 3-chloro- 4-nitro-1H-carbazole substituted 3-bromo-4-nitro-1H-carbazole and substituted 2-(chloromethyl) with 2-(chloromethyl)-6-cyclopropylpyridine hydrochloride -6-isopropylpyridine hydrochloride gave the title compound (72%).

Step C: Preparation of 3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazole-4-amine: Prepared according to Preparation D Step F using 3-chloro-1 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl 4--4-H-1H-indazole gave the title compound (63%).

Step D: Preparation of N-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2- a] Pyridin-3-carboxamide: Prepared according to Step A of Example 1 using 3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazole-4-amine Substituting 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (19%).

Step E: Preparation of N-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-isopropyl) Isopiperazin-1-yl)ethoxy)imidazo[1,2-a] pyridine-3-carboxamide: Prepared according to Step B of Example 1, using N-(3-chloro-1-(6) -cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide substituted 7-fluoro-N- (1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide Substituting 2-(4-isopropylpiperazin-1-yl)ethanol for 2-(N-morpholinyl)ethanol gave the title compound (25%). MS (APCI), positron emission scan, m/z = 613.1 (M+H).

Example 22

N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazine)- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-fluoro-4-nitro-1H-carbazole: A microwave vial equipped with a stir bar was charged with 4-nitro-1H-carbazole (1.00 g, 6.13) dissolved in 10 mL of acetonitrile. Methyl) and Select Fluor (2.82 g, 7.97 mmol). The mixture was heated at 100 ° C for 2 hours under microwave. The mixture was diluted with EtOAc (EtOAc)EtOAc. Column chromatography (EtOAc) gave EtOAc (EtOAc)

Step B: Preparation of 1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-4-nitro-1H-indazole: Prepared according to Preparation D Step D using 3-fluoro- 4-nitro-1H-carbazole substituted 3-bromo-4-nitro-1H-carbazole and substituted 2-(chloromethyl) with 2-(chloromethyl)-6-cyclopropylpyridine hydrochloride -6-isopropylpyridine hydrochloride gave the title compound (35%).

Step C: Preparation of 1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazole-4-amine : Prepared according to Preparation D Step F using 1-((6) -cyclopropylpyridin-2-yl)methyl)-3-fluoro-4-nitro-1H-carbazole substituted 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl The group 4-nitro-1H-carbazole gave the title compound (91%).

Step D: Preparation of N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-fluoroimidazo[1,2- a] Pyridin-3-carboxamide : Prepared according to Step A of Example 1 using 1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazole-4-amine Substituting 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (38%).

Step E: Preparation of N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2-(4-isopropyl) Isopiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using N-(1-((6-cyclopropyl) Pyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide substituted 7-fluoro-N- (1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide Substituting 2-(4-isopropylpiperazin-1-yl)ethanol for 2-(N-morpholinyl)ethanol gave the title compound (35%). MS (APCI), positron emission scan, m/z = 597.0 (M+H).

Example 23

(S)-N-(3-Chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(3,4- Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (S)-3,4-dimethylpiperazine-1-carboxylic acid tert-butyl ester : to (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (50 g, 0.250 Mol) A solution of formaldehyde (41.6 mL, 0.5 mol, 37% in water) and formic acid (33 mL, 0.874 mol) was added to a solution of hexanes and the mixture was warmed to 70 ° C for 16 hours, then concentrated under reduced pressure. The resulting residue was taken from EtOAc EtOAc EtOAc.

Step B: Preparation of (S)-1,2-dimethylpiperazine dihydrochloride : (S)-3,4-dimethylpiperazine-1-carboxylic acid tert-butyl ester (54 g, 0.252 mol) Dissolved in 500 mL of EtOAc and the mixture was cooled to 0 °C. HCl gas was bubbled through the solution for 20 minutes during which time a white solid formed and then dissolved. The reaction vessel was capped and stirred at ambient temperature for 16 hours during which time a white precipitate formed. The mixture was flushed with nitrogen for 10 min and a solid was collected by filtration to afford 45 g (96%)

Step C: Preparation of (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol : Prepared according to Step 2 of Example 2, using (S)-1,2-dimethylpiperazine The hydrochloride salt was replaced by 1-ethylpiperazine and potassium carbonate was replaced with sodium hydrogen carbonate to give the title compound (64%).

Step D: (S)-N-(3-Chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(3) ,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using N-(3-chloro- 1-((6-Cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (example) 21, Step AD) Substituting 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1 , 2-a]pyridine-3-carboxamide and substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-(N-morpholinyl)ethanol to give the title Compound (5%). MS (APCI), positron emission scan, m/z = 599.0 (M+H).

Example 24

(S)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2-(3,4- Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-fluoroimidazole [1,2-a]pyridine-3-carboxamide (Example 22, Step AD) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3- Methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and using (S)-2-(3,4-dimethylpiperazin-1-yl Substituting ethanol for 2-(N-morpholinyl)ethanol gave the title compound (15%). MS (APCI), positron emission scan, m/z = 583.1 (M+H).

Example 25

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl) -3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate : charged 2-chloro-3-B to a flask equipped with a reflux condenser, mechanical stirring and internal temperature probe Potassium oxy-3-oxopropan-1-en-1-carboxylate (58.70 g, 311.1 mmol) followed by 200 mL of EtOH to form a syrup. An aqueous solution of hydrogen chloride (4.862 mL, 15.56 mmol) dissolved in EtOH was then added to the slurry. The slurry was stirred for about 15 minutes, and then 4-chloropyridin-2-amine (20.00 g, 155.6 mmol) was added and the mixture was warmed to 70 °C. After about 1 hour, another 2 equivalents of a 3.2 M aqueous hydrochloric acid solution was added and the mixture was stirred at 70 ° C for 16 hours. At this time, 30 g of 2-chloro-3-ethoxy-3-oxooxyprop-1-en-1-one was further added and the mixture was stirred at 70 ° C for 2 hours to accelerate the completion of the reaction. The mixture was cooled to ambient temperature and 500 mL of water was added, then the pH was adjusted to 11 with 10% aqueous sodium carbonate. After stirring for several hours, the precipitated solid was collected by filtration and dried in vacuo to afford 31 g (yield: 88%) of desired compound.

Step B: Preparation of 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2 -a]pyridine-3-carbamide : containing 7-chloroimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (15.22 g, 67.8 mmol) and 1-(dissolved in 130 ml of THF) A round bottom flask of (6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine (Preparation D; 19.0 g, 67.8 mmol) was cooled to 0. LiHMDS (1 M in THF, 149 ml, 149 mmol) was then added by syringe over 15 min. Once the addition was complete, the reaction mixture was stirred at 0 °C for 15 min and then quenched with saturated ammonium chloride (250 mL). The mixture was extracted twice with EtOAc. Column chromatography (100% EtOAc) gave 18.6 g (60%)

Step C: Preparation of (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl) )methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : loaded into a flask equipped with a condenser with 7-chloro- N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-methyl Indoleamine (15.0 g, 32.68 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (10.34 g, 65.37 mmol, Example 23), crushed KOH (9.17 g) , 163.4 mmol) and 100 mL DMSO. The mixture was heated to 95 ° C for 22 hours. The mixture was allowed to cool to ambient temperature, 350 mL water was added and the mixture was stirred vigorously for 30 min. The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc. The material obtained was purified by column chromatography (10% MeOH / DCM / 0.5% NH ₄ OH to 15% MeOH / DCM / 0.5% NH ₄ OH) and then EtOAc. The resulting solid was collected to give 10 g (53%) MS (APCI), positron emission scan, m/z = 581.1 (M+H). [α] _D = +5.6° (c = 1.0, CHCl ₃ ).

Example 26

(S)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4) -Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Step A: Preparation of (S)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: in a pressure tube, N-(1-((6) -cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (example) 16 Step G; 0.250 g, 0.568 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.449 g, 2.84 mmol) and potassium butoxide (0.382 g, 3.41 mmol) was combined in the third butanol. The tube was sealed and warmed to 95 ° C for 16 hours and then cooled to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with aq. The crude material by column chromatography (10% MeOH / DCM / 0.5 % NH 4 OH), then triturated with ether to give 102 mg (31%) of the title compound. MS (APCI), positron emission scan, m/z = 579.1 (M+H).

Step B: Preparation of (S)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride: (S)-N-(1- ((6-Cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1- Ethyl)imidazo[1,2-a]pyridine-3-carboxamide (81.6 mg, 0.141 mmol) was dissolved in 2 mL of 4:1 DCM /MeOH. 4 M HCl/dioxane (0.071 mL, 0.282 mmol) was added and the mixture was stirred at ambient temperature for 1 hour then concentrated under vacuo and dried in vacuo for 16 s to afford 91.9 mg (100%) of the hydrochloride. [α] _D = -3.6° (c = 1.0, CHCl ₃ ).

Example 27

(R)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4) -Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Step A: Preparation of (R)-4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester: Prepared according to Example 2, Step A, using (R)-2-methyl Substituting piperazine-1-carboxylic acid tert-butyl ester to 1-ethylpiperazine gave the final product (70%).

Step B: Preparation of (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol: Prepared according to step 4 of Example 4 using (R)-4-(2-hydroxyethyl)- Substituting 2-methylpiperazine-1-carboxylic acid tert-butyl ester to replace 3-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester to give the final product (81%).

Step C: Preparation of (R)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: Prepared according to Step B of Example 1, using N-(1- ((6-Cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidine Amine (Example 16, Step AG) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carboxamide and substituting (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-(N-morpholinyl)ethanol The title compound (34%) was obtained. MS (APCI), positron emission scan, m/z = 579.1 (M+H).

Step D: Preparation of (R)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride : (R)-N-(1- ((6-Cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1- Ethyl)imidazo[1,2-a]pyridine-3-carboxamide (79.3 mg, 0.139 mmol) was dissolved in 2 mL of 4:1 DCM /MeOH. 4 M HCl/dioxane (0.069 mL, 0.278 mmol) was added and the mixture was stirred at ambient temperature for 1 hour then concentrated under vacuo and dried in vacuo for 16 s to afford 89 mg (100%) of the hydrochloride salt. [α] _D = +3.3° (c = 1.0, CHCl ₃ ).

Example 28

(R)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl) -3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

In a pressure tube, 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1] , 2-a]pyridine-3-carboxamide (Example 1 Step A), 0.300 g, 0.678 mmol), (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.536 g, 3.39 mmol) and potassium butoxide (0.456 g, 4.07 mmol) were combined in a third butanol. The tube was sealed and warmed to 95 ° C for 16 hours and then cooled to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with aq. The crude material by column chromatography (10% MeOH / DCM / 0.5 % NH 4 OH), then triturated with ether to give 136 mg (33%) of the title compound. MS (APCI), positron emission scan, m/z = 581.1 (M+H). [α] _D = -5.3° (c = 1.0, CHCl ₃ ).

Example 29

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((1-isopropyl-5-methyl-1H-pyridyl) Zyrid-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using 7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H -oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 8, Step AG) in place of 7-fluoro-N-(1-((6-isopropylpyridine)- 2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and using (S)-2-(3,4 Substituting 2-(N-morpholinyl)ethanol with dimethyl piperazine-1-yl)ethanol gave the title compound (50%). MS (APCI), positron emission scan, m/z = 585.4 (M+H).

Example 30

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl) -3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using 7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carboxamide (Example 12, Step AE) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3 -methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and using (S)-2-(3,4-dimethylpiperazine-1- Substituting ethanol for 2-(N-morpholinyl)ethanol gave the title compound (22%). MS (APCI), positron emission scan, m/z = 587.2 (M+H).

Example 31

(S)-N-(1-((6-T-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3, 4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (6-t-butylpyridin-2-yl)methanol : mp. %).

Step B: Preparation of 2-t-butyl-6-(chloromethyl)pyridine hydrochloride : Prepared according to Preparation D Step B, substituting 6-iso(6-tert-butylpyridin-2-yl)methanol Propylpyridin-2-yl)methanol gave the title compound (100%).

Step C: Preparation of 3-bromo-1 - ((6-tert-butyl-2-yl) methyl) -4-nitro -1H- indazole: prepared according to Preparation D, Step D, 2- first The title compound (55%) was obtained from the title compound (55%).

Step D: Preparation of 1-((6-t-butylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole : Prepared according to Preparation D Step E, using 3- Bromo-1-((6-t-butylpyridin-2-yl)methyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl) Methyl)-4-nitro-1H-indazole gave the title compound (64%).

Step E: Preparation of 1-((6-t-butylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine : Prepared according to Preparation D Step F using 1-( (6-T-butylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole substituted 1-((6-isopropylpyridin-2-yl)methyl) -3-Methyl-4-nitro-1H-indazole gave the title compound (73%).

Step F: Preparation of N-(1-((6-t-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1, 2-a]pyridine-3-carboxamide : Prepared according to Example 1 Step A using 1-((6-t-butylpyridin-2-yl)methyl)-3-methyl-1H-carbazole Substituting 4-amine to 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (55%).

Step G: Preparation of S)-N-(1-((6-t-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using N-(1- ((6-Tertibutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-methyl Indoleamine substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carboxamide and substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-(N-morpholinyl)ethanol to give the title compound %). MS (APCI), positron emission scan, m/z = 595.1 (M+H).

real Example 32

(S)-N-(1-((6-Cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4) -Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-bromo-6-cyclobutylpyridine: A round bottom flask was charged with anhydrous THF (50 mL), 2,6-dibromopyridine (3.00 g, 12.7 mmol), and copper iodide (0.555 g). , 2.91 mmol) and PdCl ₂ (dppf): dichloromethane adduct (1.09 g, 1.33 mmol). The mixture was flushed with argon for 10 minutes, and then cyclobutylbutyl bromide (0.5 M in THF, 30.4 mL, 15.2 mmol) was added and the mixture was stirred at ambient temperature for 2 hr. The mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic extracts were dried with sodium s Column chromatography (5% EtOAc / EtOAc) gave

Step B: Preparation of 6-cyclobutylpyridinecarboxaldehyde : Prepared according to Step 16 of Example 16 and substituting 2-bromo-6-cyclobutylpyridine to 2-bromo-6-cyclopropylpyridine to give the title compound (52%) .

Step C: Preparation of (6-cyclobutylpyridin-2-yl)methanol: mp. .

Step D: Preparation of 2-(chloromethyl)-6-cyclobutylpyridine hydrochloride : Preparation according to Preparation D Step B, substituting 6-isopropyl with (6-cyclobutylpyridin-2-yl)methanol Pyridin-2-yl)methanol gave the title compound (100%).

Step E: Preparation of 3-bromo-1-((6-cyclobutylpyridin-2-yl)methyl)-4-nitro-1H-indazole : Prepared according to Preparation D Step D using 2-(chloro Substituting 2-(chloromethyl)-6-isopropylpyridine hydrochloride with methyl)-6-cyclobutylpyridine hydrochloride afforded the title compound (68%).

Step F: Preparation of 1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole : Prepared according to Preparation D Step E using 3-bromo 1-((6-cyclobutylpyridin-2-yl)methyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl)methyl 4-nitro-1H-carbazole gave the title compound (72%).

Step G: Preparation of 1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine : Prepared according to Preparation D Step F using 1-(( 6-Cyclobutylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole substituted 1-((6-isopropylpyridin-2-yl)methyl)-3 -Methyl-4-nitro-1H-indazole gave the title compound (50%).

Step H: Preparation of N-(1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2 -a]pyridine-3-carboxamide : Prepared according to step 1 of Example 1 using 1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4 -Amine-substituted 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (40%).

Step I: Preparation of (S) -N- (1 - ( (6- cyclobutyl-2-yl) methyl) -1H- indazol-3-yl-4-yl) -7- (2- (3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using N-(1- ((6-Cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidine Amine substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a Pyridine-3-carboxamide and 2-(N-morpholinyl)ethanol were replaced with (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol to give the title compound (29%) ). MS (APCI), positron emission scan, m/z = 593.1 (M+H).

Example 33

(S)-N-(1-((6-Cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4) -Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-bromo-6-cyclopentylpyridine : Prepared according to Example 32 Step A, substituting bromobutyl bromide with bromocyclopentyl zinc to give the title compound (45%).

Step B: Preparation of (6-cyclopentylpyridin-2-yl)methanol : To a flame dried flask was placed anhydrous THF (88 mL) and cooled to -78. N-BuLi (3.54 mL, 8.85 mmol, 2.5 M in hexanes) was then weighed, then 2-bromo-6-cyclopentylpyridine (2.00 g, 8.85 mmol) of THF (10 mL) was slowly added over 15 min. ) solution. The mixture was stirred at -78 °C for 15 min and pure DMF (1.03 mL, 13.3 mmol). The mixture was stirred at -78 °C for 15 minutes, then quenched with saturated ammonium chloride solution and warmed to ambient temperature. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried with sodium s The crude material was then dissolved in methanol (50 mL), cooled to 0 deg.] C, and followed by addition of _{NaBH 4 (1.00 g, 26.5 mmol} ). After 10 minutes, the mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was concentrated under reduced EtOAc. Column chromatography (100% ethyl acetate) afforded EtOAc (EtOAc)

Step C: Preparation of 2-(chloromethyl)-6-cyclopentylpyridine hydrochloride : Prepared according to Preparation D Step B, substituting 6-isopropyl with (6-cyclopentylpyridin-2-yl)methanol Pyridin-2-yl)methanol gave the title compound (100%).

Step D: Preparation of 3-bromo-1-((6-cyclopentylpyridin-2-yl)methyl)-4-nitro-1H-indazole : Prepared according to Preparation D Step D, using 2-(chloro Substituting 2-(chloromethyl)-6-isopropylpyridine hydrochloride with methyl-6-cyclopentylpyridine hydrochloride afforded the title compound (69%).

Step E: Preparation of 1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole : Prepared according to Preparation D Step E using 3-bromo 1-((6-cyclopentylpyridin-2-yl)methyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl)methyl 4-nitro-1H-carbazole gave the title compound (67%).

Step F: Preparation of 1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine : 1-((6-cyclopentylpyridine-2) Methyl)-3-methyl-4-nitro-1H-indazole (0.470 g, 1.40 mmol) was dissolved in 14 mL of methanol. To this solution was added 20% Pd(OH) ₂ (0.470 g, water content 50%), and the reaction mixture was stirred under a hydrogen balloon for 2 hours. The mixture was filtered through a GF/F filter paper and the filtrate was concentrated to give 0.340 g (79%

Step G: Preparation of 7-chloro-N-(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2 -a]pyridine-3-carboxamide: Prepared according to step A of Example 1, substituting 7-fluoroimidazo[1,2- with ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate a] pyridine-3-carboxylic acid ethyl ester and substituted with 1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine 1-((6- Isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (56%).

Step H: Preparation of (S)-N-(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: Prepared according to Example 7 Step F using 7-chloro-N -(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidine Amine substituted 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a Pyridine-3-carboxamide and 2-((3R,5S)-3,4,5-trimethyl substituted with (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol Iptipazine-1-yl)ethanol gave the title compound (17%). MS (APCI), positron emission scan, m/z = 607.1 (M+H).

Example 34

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((4,6-dimethylpyridin-2-yl)methyl) 3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (4,6-dimethylpyridin-2-yl)methanol : Prepared according to Example 16 Step B, substituting 4,6-dimethylpyridinecarbaldehyde with 6-cyclopropylpyridinecarboxaldehyde to give the title compound (71%).

Step B: Preparation of 2-(chloromethyl)-4,6-dimethylpyridine hydrochloride : Preparation according to Preparation D Step B, substituting (4,6-dimethylpyridin-2-yl)methanol -isopropylpyridine-2-yl)methanol gave the title compound (100%).

Step C: 3-Bromo-1-((4,6-dimethylpyridin-2-yl)methyl)-4-nitro-1H-indazole : Prepared according to Preparation D Step D with 2-( Substituting chloromethyl)-4,6-lutidine hydrochloride for 2-(chloromethyl)-6-isopropylpyridine hydrochloride gave the title compound (100%).

Step D: Preparation of 1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole : Prepared according to Preparation D Step E, using 3 -Bromo-1-((4,6-dimethylpyridin-2-yl)methyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridine-2) -Methyl)-4-nitro-1H-indazole gave the title compound (59%).

Step E: Preparation of 1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine : Prepared according to Step F of Example 33, using 1- ((4,6-Dimethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole substituted 1-((6-cyclopentylpyridin-2-yl)-methyl 3-Methyl-4-nitro-1H-indazole gave the title compound (88%).

Step F: Preparation of 7-chloro-N-(1-((4,6-dimethylpyridin-2-yl)methyl)-3 -methyl-1H-indazol-4-yl)imidazo[1 , 2-a]pyridine-3-carboxamide: Prepared according to Example 1 Step A, substituting 7-fluoroimidazo[1, with ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate Ethyl 2-a]pyridine-3-carboxylate and substituted with 1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine 1- ((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (54%).

Step G: Preparation of (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((4,6-dimethylpyridine-2) -yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide: Prepared according to Step 7 of Example 7, using 7-chloro -N-(1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine- 3-carbalamine substituted 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1 , 2-a]pyridine-3-carboxamide and substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4, 5-Trimethylpiperazin-1-yl)ethanol gave the title compound (42%). MS (APCI), positron emission scan, m/z = 567.1 (M+H).

Example 35

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl) )methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(chloromethyl)-6-methylpyridine hydrochloride: Prepared according to Preparation D Step B, substituting (6-methylpyridin-2-yl)methanol to 6-isopropylpyridine- Methyl 2-methanol gave the title compound (100%).

Step B: Preparation of 3-bromo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-carbazole: Prepared according to Preparation D Step D, using 2-(chloroform) Substituting 6-methylpyridine hydrochloride to 2-(chloromethyl)-6-isopropylpyridine hydrochloride gave the title compound (56%).

Step C: Preparation of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole: Prepared according to Preparation D Step E using 3-bromo- 1-((6-Methylpyridin-2-yl)methyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl)methyl) 4-Nitro-1H-indazole gave the title compound (67%).

Step D: Preparation of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4-amine: mp . 1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-carbazole substituted 1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl Base 4-nitro-1H-carbazole gave the title compound (84%).

Step E: Preparation of 7-chloro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a] Pyridin-3-carboxamide: Prepared according to Step A of Example 1, substituting 7-fluoroimidazo[1,2-a with ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate Pyridine-3-carboxylic acid ethyl ester and replacing 1-((6-isopropyl) with 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4-amine Pyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (38%).

Step F: Preparation of (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-methylpyridine) 2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide: Prepared according to Step 7 of Example 7, using 7-chloro-N- (3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide 7-Chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-carbalamine and substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5-trimethylperidazole Pyrazin-1-yl)ethanol gave the title compound (11%). MS (APCI), positron emission scan, m/z = 553.1 (M+H).

real Example 36

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-ethylpyridin-2-yl)methyl)- 3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-vinylpicolinate : Prepared according to Preparation C Step E, substituting potassium trifluoro(vinyl)borate with potassium trifluoro(prop-1-en-2-yl)borate to give the title compound (99%).

Step B: Preparation of ethyl 6-ethylpicolinate : Ethyl 6-vinylpicolinate (4.70 g, 26.5 mmol) was dissolved in 100 mL of ethanol. 20% Pd(OH) ₂ /carbon (1 g, 50% water) was added thereto and the mixture was stirred under a hydrogen balloon for 2 hours. The mixture was flushed with EtOAc (EtOAc)EtOAc.

Step C: Preparation of (6-ethylpyridin-2-yl)methanol : mp. %).

Step D: Preparation of 2-(chloromethyl)-6-ethylpyridine hydrochloride : Preparation according to Preparation D Step B, substituting 6-isopropylpyridine with (6-ethylpyridin-2-yl)methanol Methyl 2-methanol gave the title compound (100%).

Step E: Preparation of 3-bromo-1-((6-ethylpyridin-2-yl)methyl)-4-nitro-1H-carbazole : Prepared according to Preparation D Step D, using 2-(chloroform) Substituting -6-ethylpyridine hydrochloride to 2-(chloromethyl)-6-isopropylpyridine hydrochloride gave the title compound (72%).

Step F: Preparation of 1-((6-ethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole : Prepared according to Preparation D Step E using 3-bromo- 1-((6-ethylpyridin-2-yl)methyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl)methyl) 4-Nitro-1H-indazole gave the title compound (70%).

Step G: Preparation of 1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine : mp. -ethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole substituted 1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl The benzyl 4-nitro-1H-carbazole gave the title compound (93%).

Step H: Preparation of 7-chloro-N-(1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2- a] Pyridin-3-carboxamide : Prepared according to Step A of Example 1, substituting 7-fluoroimidazo[1,2-a with ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate Pyridine-3-carboxylic acid ethyl ester and 1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine substituted 1-((6-isopropyl) Pyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (45%).

Step I: Preparation of (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-ethylpyridin-2-yl)) Methyl)-3-methyl-1H-indazol-4-yl)imidazo [1,2-a]pyridine-3-carboxamide : Prepared according to Example 7 Step F using 7-chloro-N- (1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide 7-Chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-carbalamine and substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5-trimethylperidazole Pyrazin-1-yl)ethanol gave the title compound (27%). MS (APCI), positron emission scan, m/z = 567.1 (M+H).

Example 37

N-(1-((6-Seconbutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((S)-3, 4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the procedure of Example 33, Steps A to H, in which a second butyl bromide was substituted for the brominated cyclopentyl zinc as a starting material. MS (APCI), positron emission scan, m/z = 595.1 (M+H).

Example 38

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((5-propylpyridin-2-yl) )methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the procedure of Example 33, Steps B to H, using 2-bromo-5-propylpyridine instead of 2-bromo-6-cyclopentylpyridine. MS (APCI), positron emission scan, m/z = 581.1 (M+H).

Example 39

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-isopropylpyridin-2-yl)methyl) -3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 5-(prop-1-en-2-yl)pyridinecarboxaldehyde : mp. .

Step B: Preparation of (5-isopropylpyridin-2-yl)methanol : 5-(prop-1-en-2-yl)pyridinecarboxaldehyde (0.600 g, 4.08 mmol) was dissolved in methanol (15 mL). Pd(OH) ₂ (0.600 mg, 20% catalyst/carbon, 50% by weight water) was added thereto and the mixture was hydrogenated under a hydrogen balloon for 2 hours. The mixture was filtered through EtOAc / EtOAc (EtOAc)

Step C: Preparation of (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-isopropylpyridin-2-yl) Methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : Example 39 was prepared according to Example 33, Steps C to H, In step C, (5-isopropylpyridin-2-yl)methanol was used instead of (6-cyclopentylpyridin-2-yl)methanol. MS (APCI), positron emission scan, m/z = 581.1 (M+H).

real Example 40

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isobutylpyridin-2-yl)methyl) -3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

The preparation was carried out according to the procedure of Example 33, Steps A to H, in which the butyl bromide bromide was used instead of the cyclopentyl zinc bromide. MS (APCI), positron emission scan, m/z = 595.2 (M+H).

Example 41

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-fluoro-6-isopropylpyridin-2-yl) )methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-bromo-5-fluoropicolinic acid : 2-Bromo-3-fluoro-6-methylpyridine (3.60 g, 18.9 mmol) was dissolved in 10 mL pyridine in a pressure tube. 50 mL of water was added thereto and the mixture was warmed to 85 °C. Potassium permanganate (5.99 g, 37.9 mmol) was added, the tube was capped, and the mixture was stirred at 85 ° C for 48 hours. The mixture was filtered through GF/F filter paper and the filtrate was concentrated under reduced pressure to approximately half volume. The residue was acidified to aq. The combined organic extracts were dried with sodium

Step B: Preparation of 1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole: according to Preparation C Steps D to F and Preparation of Steps E, D and E were carried out in the preparation of Step C, using 6-bromo-5-fluoropicolinic acid in place of 6-chloropicolinic acid as starting material to give the title compound.

Step C: Preparation of 1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine: Prepared according to step 1-((5-Fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole substituted 1-((6-cyclopentylpyridine-2 -Methyl)-3-methyl-4-nitro-1H-indazole gave the title compound (87%).

Step D: Preparation of (S)-4-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)pyridin-2-amine: 4-chloropyridine-2 in a pressure tube - amine (0.500 g, 3.89 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (1.23 g, 7.78 mmol) and crushed potassium hydroxide (0.546 g, 9.72 mmol) was combined in 8 mL DMSO and heated to 95 ° C for 16 hours. The mixture was then diluted with EtOAc (EtOAc) (EtOAc) Column chromatography (5% MeOH / DCM) gave 0.484 g (50%

Step E: Preparation of ethyl (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate: Preparation C Step C was carried out by substituting (S)-4-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)pyridin-2-amine for 4-fluoropyridin-2-amine The title compound (25%) was obtained.

Step F: Preparation of (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-fluoro-6-isopropylpyridine) 2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step A of Example 1, using ( S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester substituted 7-fluoroimidazo[ Ethyl 1,2-a]pyridine-3-carboxylate with 1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4- Amine-substituted 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (46%). MS (APCI), positron emission scan, m/z = 599.2 (M+H).

Example 42

(S)-7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-(2-(6-methylpyridine-2) -yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-bromo-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-indazole : Prepared according to Preparation D Step D using 2-( Substituting 2-(chloromethyl)-6-isopropylpyridine hydrochloride, 2-bromoethyl)-6-methylpyridine hydrobromide afforded the title compound (31%).

Step B: Preparation of 3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-carbazole : Prepared according to Preparation D, Step E, using 3- Bromo-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl) Methyl)-4-nitro-1H-indazole gave the title compound (83%).

Step C: Preparation of 3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-amine: Prepared according to Example 33 Step F 1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-carbazole substituted 1-((6-cyclopentylpyridin-2-yl)methyl) 3-Methyl-4-nitro-1H-indazole gave the title compound (68%).

Step D: Preparation of 7-chloro-N-(3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide: Prepared according to Example 1 Step A, substituting 7-fluoroimidazo[12-a with ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate Pyridine-3-carboxylic acid ethyl ester and replacing 1-((6-) with 3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazole-4-amine Isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine gave the title compound (100%).

Step E: Preparation of (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-(2-(6-A) Pyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide: Prepared according to Example 7 Step F using 7-chloro- N-(3-Methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3- Methionine Substituted 7-Chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2 -a]pyridine-3-carbamide and substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5- Trimethylpiperazin-1-yl)ethanol gave the title compound (6%). MS (APCI), positron emission scan, m/z = 567.1 (M+H).

Example 43

(S)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-(2- (3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-fluoro-2-methyl-3-nitrobenzoic acid : 2-fluoro-6-methylbenzoic acid (40 g, 0.26 mol) was dissolved in 320 mL of sulfuric acid and cooled to -15 ° C . To this was added 14 mL of fuming nitric acid dissolved in 60 mL of sulfuric acid over a period of 10 minutes. Once the addition was complete, the mixture was stirred at 0 ° C for 1 hour, then poured into ice water and stirred. The resulting solid was collected and purified EtOAc mjjjjjjj

Step B: Preparation of methyl 6-fluoro-2-methyl-3-nitrobenzoate : 6-fluoro-2-methyl-3-nitrobenzoic acid (21.2 g, 0.107 mol), powdered potassium carbonate Methyl iodide (37.8 g, 0.266 mol) was added to a mixture of (36.8, 0.266 mol) in DMF (200 mL). The mixture was stirred at ambient temperature for 16 h then diluted with water and EtOAc. The combined organic extracts were washed with brine w... Column chromatography (20% ethyl acetate / hexane) gave 12.6 g (56%)

Step C: Preparation of methyl 3-amino-6-fluoro-2-methylbenzoate : Prepared according to step F of Example 33, substituted with methyl 6-fluoro-2-methyl-3-nitrobenzoate -((6-Cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole gave the title compound (95%).

Step D: Preparation of methyl 5-fluoro-1H-indazole-4-carboxylate: Dissolving methyl 3-amino-6-fluoro-2-methylbenzoate (7.50 g, 0.041 mol) in 150 mL of acetic acid . Acetic anhydride (14.6 g, 0.143 mol) was added thereto and the mixture was heated to 75 °C. Sodium nitrite (11.3 g, 0.164 mol) was added portionwise to the reaction mixture (gas evolution was observed). The mixture was stirred at 75 ° C for 16 hours, then cooled to ambient temperature and then poured into a cold 10% aqueous potassium carbonate solution. This material was extracted twice with EtOAc. Column chromatography (1:1 EtOAc / hexanes) gave 0.48 g of &lt;EMI&gt; The crude material was then added to 5 mL of 4 M HCl / dioxane and 15 mL of methanol in a pressure tube and heated to 60 ° C for 2 hours. The mixture was concentrated under reduced pressure and the obtained solid was dissolved in 10% aqueous potassium carbonate /EtOAc. The organic layer was separated, dried over sodium sulfate dried

Step E: Preparation of methyl 3-bromo-5-fluoro-1H-indazole-4-carboxylate: methyl 5-fluoro-1H-indazole-4-carboxylate (0.475 g, 2.45 mmol) in 25 mL DMF N-bromosuccinimide (0.566 g, 3.18 mmol) was added to the solution. This mixture was stirred at ambient temperature for 1 hour and then quenched with water. The mixture was extracted with EtOAc. Column chromatography (1:1 EtOAc / hexanes) afforded:

Step F: Preparation of methyl 3-bromo-1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-1H-indazole-4-carboxylate: Prepared according to Preparation D Step D, Substitution of 3-bromo-5-fluoro-1H-indazole-4-carboxylic acid methyl ester for 3-bromo-4-nitro-1H-carbazole with 2-(chloromethyl)-6-cyclopropylpyridine salt The acid salt was replaced by 2-(chloromethyl)-6-isopropylpyridine hydrochloride to give the title compound (77%).

Step G: Preparation of methyl 1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylate : Prepared according to Preparation D Step E Substituting 3-bromo-1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-1H-indazole-4-carboxylic acid methyl ester for 3-bromo-1-((6- Isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole gave the title compound (73%).

Step H: Preparation of 1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylic acid : 1-(( Methyl 6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylate (0.310 g, 0.913 mmol) was taken in 1M in 10 mL THF Aqueous lithium hydroxide (1.83 mL, 1.83 mmol) over 16 hours. The mixture was then diluted with 1M aqueous HCl (br. to pH 4) and extracted twice with EtOAc. The combined organic extracts were dried with sodium s

Step I: Preparation of 1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-amine : 1-((6-cyclopropyl) Pyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylic acid (0.205 g, 0.630 mmol) was dissolved in 6 mL DMF. Diphenylphosphoryl azide (0.260 g, 0.945 mmol) and TEA (0.263 mL, 1.89 mmol) were added and the mixture was stirred at ambient temperature for 1.5 h. Water (5 mL) was added and the mixture was warmed to 80 ° C for 2 h then stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine w... Column chromatography (1:1 EtOAc: hexanes) elute

Step J: Preparation of N-(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-fluoroimidazole [1,2-a]pyridine-3-carboxamide : Prepared according to Example 1 Step A using 1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl Substituting 1-H-oxazol-4-amine to 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine to give the title compound (6.5% ).

Step K: Preparation of (S)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7 -(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using N -(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2- a] Pyridine-3-carboamine substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide and substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-(N-morpholinyl) Ethanol gave the title compound (20%). MS (APCI), positron emission scan, m/z = 597.1 (M+H).

Example 44

7-(2-(4-Isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)) -1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Step A: Preparation of ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy) imidazo[1,2-a]pyridine-3-carboxylate: (E) Potassium 2-chloro-3-ethoxy-3-oxooxyprop-1-en-1-carboxylate (Preparation B; 41.32 g, 219.0 mmol) was suspended (with vigorous magnetic stirring) over anhydrous diethyl ether (0.3 M, 6 N sulfuric acid (18.25 ml, 109.5 mmol) was added to 365 mL). Additional water (about 100 mL) was added to aid phase separation. When the pH of the lower (water) layer fell below 3, the ether layer was separated. The aqueous layer was extracted with diethyl ether (400 mL). The combined ether phases were dried over sodium sulfate and magnesium sulfate for 10 min. The solution was filtered and concentrated under reduced pressure while the water bath temperature did not exceed 20 °C. An oil was obtained which solidified after drying under high vacuum overnight. This solid was dissolved in anhydrous EtOH (0.3 M, 360 mL). &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&& The mixture was heated at 65 ° C for 18 hours under nitrogen. After allowing the mixture to cool, the resulting suspension was evaporated to dryness. The resulting solid was shaken with THF and collected by filtration then dried in vacuo. The crude material (isolated as the hydrochloride salt) was combined with water (400 mL) and ethanol (200 mL). Sodium bicarbonate (20 g) was added and stirred overnight. The suspension was evaporated to dryness under vacuum. The solid was shaken in EtOAc / THF and separated by filtration. The solid was then washed with a larger volume of ethyl acetate and THF under gravity. The filtrate was further dried over sodium sulfate and magnesium sulfate, filtered and evaporated This material was triturated with 2:1 diethyl ether-hexane and the obtained solid was collected by filtration to give 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2- a] ethyl pyridine-3-carboxylate (23.46 g, 59% yield).

Step B: Preparation of lithium 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate: soluble in water (30 mL) Adding hydrogen to ethyl 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (5.68 g, 15.8 mmol) Lithium oxide hydrate (0.67 g, 16.0 mmol). The reaction was heated to 95 ° C for 4 hours. The reaction was cooled to ambient temperature and hydrogen chloride (0.0394 mL, 4M in dioxane) was added to the mixture and stirred for 10 min. The water was removed in vacuo to afford title compound (5.43 g).

Step C: Preparation of 2-(chloromethyl)-5-(trifluoromethyl)pyridine hydrochloride : Prepared according to Preparation D Step B using (5-(trifluoromethyl)pyridin-2-yl)methanol Substituting isopropylpyridin-2-yl)methanol to give the title compound (100%).

Step D: Preparation of 3-bromo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole : Prepared according to Preparation D Step D, using 2 -(Chloromethyl)-5-(trifluoromethyl)pyridine hydrochloride was substituted for 2-(chloromethyl)-6-isopropylpyridine hydrochloride to give the title compound (59%).

Step E: Preparation of 3-methyl-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-carbazole : Prepared according to Preparation D Step E, 3-bromo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridine) 2-yl)methyl)-4-nitro-1H-indazole gave the title compound (42%).

Step F: Preparation of 3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole-4-amine : Prepared according to Preparation D Step F, using 3 -Methyl-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-carbazole substituted 1-((6-isopropylpyridin-2-yl) Methyl)-3-methyl-4-nitro-1H-indazole gave the title compound (91%).

Step G: Preparation of 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((5-(trifluoromethyl)pyridine-2) -yl)methyl)-1H-indazol-4-yl)imidazo [1,2-a]pyridine-3-carboxamide : 7-(2-(4-isopropylpiperazin-1- Lithium ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.746 g, 2.204 mmol) was dissolved in 16 mL anhydrous NMP. 2,4,6-Trichlorobenzamide chloride (0.538 g, 2.20 mmol) was added thereto and the mixture was stirred at ambient temperature for 30 min. Add 3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.500 g, 1.63 mmol) and warm the mixture to 90 °C It lasted for 16 hours and then cooled to ambient temperature. Water (50 mL) was added and the mixture was extracted with EtOAc. The extract was washed with aq. Column chromatography (7% MeOH / DCM / 0.5 % NH 4 OH) to give 0.112 g (11%) of final compound. MS (APCI), positron emission scan, m/z = 622.2 (M+H).

Example 45

7-(2-(4-Isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)) -1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(chloromethyl)-6-(trifluoromethyl)pyridine hydrochloride : Preparation according to Preparation D Step B using (6-(trifluoromethyl)pyridin-2-yl)methanol Substituting isopropylpyridin-2-yl)methanol to give the title compound (100%).

Step B: Preparation of 3-bromo-4-nitro-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole : Prepared according to Preparation D Step D, using 2 -(Chloromethyl)-6-(trifluoromethyl)pyridine hydrochloride was substituted for 2-(chloromethyl)-6-isopropylpyridine hydrochloride to give the title compound (81%).

Step C: Preparation of 3-methyl-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole : Prepared according to Preparation D Step E, 3-bromo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridine) 2-yl)methyl)-4-nitro-1H-indazole gave the title compound (42%).

Step D: Preparation of 3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole-4-amine : Prepared according to Preparation D Step F, using 3 -Methyl-4-nitro-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-carbazole substituted 1-((6-isopropylpyridin-2-yl) Methyl)-3-methyl-4-nitro-1H-indazole afforded the title compound.

Step E: Preparation of 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid : ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (8 g; 44.4 mmol) Tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL) were combined. Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. The mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure to remove tetrahydrofuran and ethanol. 2 N hydrochloric acid was added to the aqueous mixture to adjust to pH 3. A white precipitate formed which was filtered and dried <RTI ID=0.0>

Step F: Preparation of 7-fluoro-N-(3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyridine-3-carboxamide : Prepared according to Step G of Example 44, substituting 7-(2-(4-(4-)) with 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid Lithium propyl piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate with 3-methyl-1-((6-(trifluoromethyl)pyridine-2) -yl)methyl)-1H-indazole-4-amine substituted 3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole-4- The title compound (20%) was obtained.

Step G: Preparation of 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-(trifluoromethyl)pyridine-2) -yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step B of Example 1, using 7-fluoro-N-(3) -methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidine Amine substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a Pyridine-3-carbamide and 2-(N-morpholinyl)ethanol were replaced with 2-(4-isopropylpiperazin-1-yl)ethanol to give the final compound (41%). MS (APCI), negative electron scan, m/z = 620.4 (MH).

Example 46

(S)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3-A) Piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (S)-4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylic acid benzyl ester : Prepared according to step 2 of Example 2 using (S)-2-methylpiperazine Benzyl-l-carboxylate was substituted for 1-ethylpiperazine and potassium carbonate was replaced with sodium hydrogencarbonate to give the title compound (61%).

Step B: Preparation of (S)-2-(3-methylpiperazin-l-yl)ethanol : Prepared according to step 33 of Example 33 using (S)-4-(2-hydroxyethyl)-2- Substituting benzyl piperazine-1-carboxylate for 1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole afforded the title compound (77% ).

Step C: Preparation of (S)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (3-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to Step 7 of Example 7, using (S)-2-(3 Substitution of 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol with -methylpiperazin-1-yl)ethanol gave the final compound (19%). MS (APCI), positron emission scan, m/z = 567.1 (M+H).

Example 47

N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1 Step B using N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazole And [1,2-a]pyridine-3-carboxamide substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indole Zin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(N-morpholinyl)ethanol substituted with 2-(4-methylpiperazin-1-yl)ethanol The final product (45%) was obtained. MS (APCI), positron emission scan, m/z = 565.3 (M+H).

Example 48

N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-A) Piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Step A: Preparation of (1-isopropyl-1H-pyrazol-3-yl)methanol: The commercially available ethyl 1-isopropyl-1H-pyrazole-3-carboxylate was dissolved in diethyl ether and the solution was cooled. To 0 ° C and 1 M lithium aluminum tetrahydrofuran solution was added. After stirring for 3 hours, the reaction mixture was poured into a cold 30% aqueous solution of Rochelle and stirred for 1 hour. The resulting mixture was extracted twice with diethyl ether. The combined organic extracts were washed with EtOAc EtOAc m.

Step B: Preparation of 3-(chloromethyl)-1-isopropyl-1H-pyrazole hydrochloride: (1-isopropyl-1H-pyrazol-3-yl)methanol was dissolved in dichloromethane And add SOCl ₂ (2 equivalents). The resulting mixture was stirred overnight then concentrated in vacuo to give the desired compound.

Step C: Preparation of 3-bromo-1-((1-isopropylpyrazol-3-yl)methyl)-4-nitro-1H-indazole: Prepared according to Step J of Example 1 using 3-( The chloromethyl)-1-isopropyl-1H-pyrazole hydrochloride was substituted for 2-(chloromethyl)-6-isopropylpyridine hydrochloride to give the desired compound (75% yield).

Step D: Preparation of 3-methyl-1-((1-isopropylpyrazol-3-yl)methyl)-4-nitro-1H-indazole: Prepared according to Step K of Example 1 using 3- Brom-1-((1-isopropylpyrazol-3-yl)methyl)-4-nitro-1H-carbazole substituted 3-bromo-1-((6-isopropylpyridin-2-yl) Methyl)-4-nitro-1H-carbazole gave the desired compound (56%).

Step E: Preparation of 3-methyl-1-((1-isopropylpyrazol-3-yl)methyl)-4-amino-1H-indazole: Prepared according to Example 1 Step L, using 3- Methyl-1-((1-isopropylpyrazol-3-yl)methyl)-4-nitro-1H-carbazole substituted 3-methyl-1-((6-isopropylpyridine-2) -Methyl)-4-nitro-1H-indazole gave the desired compound (77%).

Step F: Preparation of 7-chloro-N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazole [1,2-a]pyridine-3-carboxamide: 3-methyl-1-((1-isopropylpyrazol-3-yl)methyl)-4-amino-1H-carbazole (1 eq.) and ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (Example 7 Step D; 1 eq.) were dissolved in dry THF (0.2 M) and the solution was cooled to 0 ° C . Lithium bis(trimethyldecyl)amine (2.3 equivalents) was added slowly and the resulting mixture was allowed to warm to ambient temperature overnight. The THF was removed under vacuum and the residue was partitioned between water and ethyl acetate. The lower aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were combined, dried over sodium s

Step G: Preparation of N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2- (4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride: Prepared according to Example 7 Step F using 7-chloro- N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-carbamamine substituted 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[ 1,2-a]pyridine-3-carboxamide and 2-(4-methylpiperazin-1-yl)ethanol substituted 2-((3R,5S)-3,4,5-trimethylper Pyrazin-1-yl)ethanol. The hydrochloride salt was prepared by the compound in 4M EtOAc/EtOAc (20 EtOAc) MS (APCI), positron emission scan, m/z = 556.3 (M+H).

Example 49

N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-iso) Propyl piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 48 Step G, substituting 2-(4-isopropylpiperazin-1-yl)ethanol in 2-(4-methylpiperazin-1-yl)ethanol to give the final product (17%). MS (APCI), positron emission scan, m/z = 584.3 (M+H).

Example 50

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(6-methylpyridin-3-yl)imidazole And [1,2-a]pyridine-3-carboxamide dihydrochloride

Step A: Preparation of methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate : Dissolving 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (4.93 g, 20.5 mmol) In 80 mL of anhydrous dichloromethane. To this solution was added grass chloroform (20.5 mL, 40.9 mmol, 2 M in dichloromethane), followed by a few drops of DMF. The mixture was stirred at ambient temperature for 16 hours then concentrated under reduced pressure. The resulting material was dissolved in 100 mL of methanol and stirred at ambient temperature for 6 hr then concentrated. The obtained material was suspended in saturated aqueous sodium hydrogen sulfate and extracted with dichloromethane and EtOAc. The organics were combined, dried over sodium sulfate and evaporated

Step B: Preparation of 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a] Pyridin-3-carboxamide: Prepared according to Step A of Example 1, using 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4-amine Substituting 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine and using 7-bromoimidazo[1,2-a]pyridine-3 Substituting methyl formate to ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate gave the title compound (62%).

Step C: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(6-methylpyridine-3 -yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride: 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl) Methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.0486 g, 0.102 mmol) was dissolved in 2 mL of 1:1 DME:DMF. 6-Methylpyridin-3-ylboronic acid (0.0210 g, 0.153 mmol), Pd(dppf)Cl ₂ (5 mol%) and 2M aqueous sodium carbonate solution (153 μL, 0.306 mmol) were added thereto. Nitrogen gas was bubbled through the mixture for 5 minutes and then the mixture was heated to 90 °C for 16 hours. The reaction mixture was diluted with EtOAc and the obtained precipitate was removed by filtration. The filtrate was washed with water and brine, dried over sodium sulfate The crude material was subjected to reverse phase chromatography followed by 4 M HCl / dioxane to give the final product. MS (APCI), positron emission scan, m/z = 488.2 (M+H).

Example 51

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1,2,3,6-tetrahydropyridine 4-yl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride

7-Bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-Methylguanamine (Example 50, Step AB; 0.0815 g, 0.171 mmol) was dissolved in 2 mL 1:1 (DME: DMF). To which 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-formic acid was added Third butyl ester (0.0795 g, 0.257 mmol), Pd(dppf)Cl ₂ (5 mol%) and 2 M aqueous sodium carbonate solution (256 μL, 0.513 mmol). Nitrogen gas was bubbled through the solution for 5 minutes and then the reaction mixture was heated to 90 °C for 16 hours. The reaction mixture was then diluted with EtOAc EtOAc. The crude material was purified by reverse phase chromatography to give 4-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylamine Methylmercapto) Imidazo[1,2-a]pyridin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, treated with 4 M HCl / dioxane Title product. MS (APCI), positron emission scan, m/z = 478.2 (M+H).

Example 52

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperidin-4-yl)imidazo[1] ,2-a]pyridine-3-carbendamine trihydrochloride

4-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylaminecarboxamido)imidazo[1,2- a] Pyridin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Example 51; 0.037 g, 0.064 mmol) was dissolved in 6 mL of methanol and 1.3 mL of 6 N HCl. In a propanol solution. 10% Pd/C (0.075 g) was added and the mixture was hydrogenated under a hydrogen balloon for 2 hours. The diatomaceous earth was added, and then the mixture was filtered through GF/F filter paper and the filtrate was concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc) MS (APCI), positron emission scan, m/z = 480.3 (M+H).

Example 5 3

7-Fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine- 3-methylamine

7-Fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (0.081 g, 0.449 mmol) was dissolved in sulphur chloride (2 mL). A few drops of DMF were added thereto and the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the obtained solid was dissolved in 3 mL of 1:2 DCM: DMF. To this was added 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.114 g, 0.451 mmol) followed by dipropylethylamine (235) μL, 1.35 mmol). The mixture was stirred at ambient temperature for 2 hours and then diluted with water (22 mL) while stirring for a few hours to form a beige precipitate. The solid was collected to give 0.100 g (54%) MS (APCI), positron emission scan, m/z = 415.2 (M+H).

Example 54

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(pyrrolidin-1-yl)imidazo[1] ,2-a]pyridine-3-carbendamine dihydrochloride

7-Fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-Methylguanamine (Example 53; 0.0144 g, 0.0347 mmol) was suspended in n-butanol (0.2 mL). Pyrrolidine (7.25 μL, 0.0869 mmol) was added thereto and the mixture was heated to 120 ° C for 12 hours. The mixture was concentrated under reduced pressure. The material was dissolved in EtOAc (EtOAc)EtOAc. The material was treated with 2M EtOAc in diethyl ether to afford N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7- (Pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride. MS (APCI), positron emission scan, m/z = 466.3 (M+H).

Example 55

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2- (pyrrolidin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Prepared according to Example 1 Step B using 7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazole [1,2-a]pyridine-3-carboxamide (Example 53) substituted 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl- 1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(N-morpholinyl)ethanol was replaced with 2-(pyrrolidin-1-yl)ethanol. The crude material was purified by EtOAc (EtOAc) elute MS (APCI), positron emission scan, m/z = 510.0 (M+H).

Example 56

4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylaminecarboxy) imidazo[1, 3-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester

Add 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (0.278 g, 1.21) to a solution of 0.4 M potassium tert-butoxide (0.068 g, 0.606 mmol) in THF cooled in ice water. Mm). The reaction was stirred for 10 min then added 7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole in 2 mL of NMP. 4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 53; 0.100 g 0.241 mmol). The reaction was allowed to warm to ambient temperature and stirred for 1 hour then heated to 60 ° C and stirred for 12 h. The THF was removed by rotary evaporation and the mixture was heated to 120 ° C for 5 hours. An additional 1 equivalent of potassium t-butoxide was added and the mixture was heated for an additional 3 hours. The reaction was quenched with water and extracted with EtOAc. The extract was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative thin layer chromatography and reverse phase chromatography gave the title compound. MS (APCI), positron emission scan, m/z = 625.0 (M+H).

Example 57

7-(2-Hydroxyethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1] ,2-a]pyridine-3-carbendamine dihydrochloride

Prepared according to Example 57, substituting 2-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester with 2-t-butoxyethanol to give 7-(2-t-butoxyethoxy) -N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3- Formamide. This material was treated with EtOAc (EtOAc) elute MS (APCI), positron emission scan, m/z = 457.2 (M+H).

Example 58

7-(2,3-Dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine : at 145 ° C, will contain 4- Chloro-2-pyridinamine (4 g, 31.2 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (8.4 g, 60.6 mmol) and sodium (1.46 g, 63.5 mmol) of the sealed tube was heated for 8 hours. The mixture was cooled to ambient temperature and water (25 mL) and dichloromethane (50 mL). The organic phase was separated, dried over sodium sulfate and evaporated. The residue was purified by chromatography to give 4-((2,2-dimethyl-l-l-dioxolan-4-yl)methoxy) as a pale yellow solid. Pyridin-2-amine (5.6 g).

Step B: Preparation of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid Ester: 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine in a reaction flask under a dry nitrogen atmosphere (5.6 g, 0.025 mol) was mixed with ethanol (60 mL). A solution of ethyl 2-chloro-3-oxopropionate (5% benzene solution; 93 mL; solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60 ° C under nitrogen for 2 hours. After allowing the mixture to cool, the solvent was removed in vacuo to afford a brown solid. The solid was mixed with ethyl acetate (200 mL) and sodium bicarbonate solution (100 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted with ethyl acetate (50 mL). The combined ethyl acetate extracts were dried with sodium s The crude material was dissolved in ethyl acetate (br.) (br.) Ethyl 4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate (5.76 g).

Step C: Preparation of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid : Ethyl 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.8 g, 5.63 mmol) and lithium hydroxide monohydrate (0.284 g, 6.75 mmol) were combined in a flask containing tetrahydrofuran/ethanol/water (1:2:1, 56 mL). After stirring overnight at ambient temperature, the solvent was removed in vacuo to afford a yellow gum. Water (20 mL) and dichloromethane were added. The aqueous layer was separated and cooled in an ice-water bath, then adjusted to pH 4 with 20% EtOAc. A precipitate formed and was collected by filtration. The solid was washed with a small amount of water (5 mL) and dried in vacuo toield of <RTI ID=0.0>((2, </RTI></RTI></RTI><RTIgt; [1,2-a]pyridine-3-carboxylic acid (1.3 g).

Step D: Preparation of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-) Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide: 7-((2,2-dimethyl) -1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (66 mg, 0.23 mmol) dissolved in dichloromethane (1 mL) A solution of 2 M chlorophyll chloride (0.12 mL, 0.25 mmol) and 1 drop of dimethylformamide were added. The mixture was stirred at ambient temperature for 1 hour, followed by the addition of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (57 mg, 0.23 mmol). Diisopropylethylamine (0.08 mL, 0.46 mmol), and then the mixture was stirred overnight. The crude mixture was purified using preparative thin layer chromatography (2 s., 20×20 cm, 1 mm) eluting with 10% methanol/dichloromethane to afford 7-((2,2-) Methyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H -oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (12 mg).

Step E: Preparation of 7-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4 -yl)imidazo[1,2-a]pyridine-3-carboxamide: 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy -N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3 -Procarbamide (11 mg, 0.02 mmol) was dissolved in 50% trifluoroacetic acid in water and stirred at ambient temperature for 1 hour. Concentrate under high vacuum and dry for 1 hour before treatment with an excess of 2 M aqueous hydrochloric acid. The solution was stirred for 1 hour and then concentrated to give 7-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)) Base-1H-oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (8 mg). MS m/z 487.2 (M+1, APCI+).

Example 59

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(N-morpholinyl)ethoxylate Imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(2-(N-morpholinyl)ethoxy)pyridin-2-amine : Treatment of 2-(N-morpholinyl) with sodium (116 mg, 5.0 mmol) in a sealed tube Ethanol (2.2 g, 16.8 mmol) was stirred at ambient temperature until homogeneous. 4-Chloropyridin-2-amine (1.1 g, 8.9 mmol) was added and the reaction was heated to 145 ° C and stirred in a sealed tube for 10 h. The mixture was cooled to ambient temperature and then diluted with ethyl acetate and water. After separating the layers, the aqueous solution was extracted twice with ethyl acetate. The reaction mixture was concentrated to give a viscous oil, which was purified on a Biotage 40+ s s s s s s s s s s s s s Ethoxy)pyridin-2-amine, which was further dried under high vacuum and solidified (1.4 g).

Step B: Preparation of ethyl 7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate : 4-(2-() in a round bottom flask N-morpholinyl)ethoxy)pyridin-2-amine (1.37 g, 6.14 mmol) was dissolved in ethanol (20 mL). Ethyl 2-chloro-3-oxopropionate (5% benzene solution; 30 mL; solution from Toronto Research Chemicals Inc.) was added and the mixture was heated to reflux overnight with stirring. The reaction was concentrated to give a beige solid (1.31 g). The solid was purified on a ruthenium dioxide column, eluting with 800 mL of 50-100% ethyl acetate / hexanes, then eluting with 10% methanol / dichloromethane to afford 7-(2-(N) -morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (1 g).

Step C: Preparation of lithium 7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate : 7-(2-(N-morpholinyl) Ethyl oxy)imidazo[1,2-a]pyridine-3-carboxylate (1 g, 3.13 mmol) was dissolved in tetrahydrofuran / water (4:1, 0.5 M). Lithium hydroxide monohydrate (131 mg, 3.13 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was then diluted with tetrahydrofuran and concentrated. The resulting material was dried under high vacuum for 6 hr to afford crystals (yield: 7-(2-(N-morpholinyl)ethoxy) imidazo[1,2-a]pyridine-3-carboxylate (979 mg) as a pale yellow solid.

Step D: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(N-morpholine) Ethyl )imidazo[1,2-a]pyridine-3-carboxamide: 7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine Lithium-3-carboxylate (0.055 g, 0.186 mmol) was dissolved in dimethylformamide (0.6 mL). O-(7-azabenzotriazol-1-yl)-N,N,N' , N'-tetramethylurea hexafluorophosphate (53 mL, 0.17 mmol), 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4- The amine (Example 35, Step AD; 0.042 g, 0.167 mmol) and diisopropylethylamine (0.058 mL, 0.334 mmol) were combined in a 1 dram vial. The mixture was stirred overnight at ambient temperature. The crude mixture was purified using preparative thin layer chromatography (c. s., 20×20 cm, 1 mm) eluting with 10% methanol/dichloromethane to afford N-(3-methyl-1). -((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(N-morpholinyl)ethoxy)imidazo[1,2- a] Pyridine-3-carboamine (6 mg). MS m/z 526.1 (M+, APCI+).

Example 60

7-(2-(Dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4- Imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(2-(dimethylamino)ethoxy)pyridin-2-amine: Treatment of 2-dimethylaminoethanol with sodium (2.7 g, 11.7 mmol) in a sealed tube 34.8 g, 39.0 mmol) and stirred at ambient temperature until homogeneous. 4-Chloropyridin-2-amine (5 g, 3.9 mmol) was added and the reaction was heated to 150 ° C and stirred in a sealed tube for 8 h. The mixture was cooled to ambient temperature then concentrated and EtOAc (EtOAc) (EtOAc) The combined wet-mills were concentrated and purified by column chromatography to afford 4-(2-(dimethylamino)ethoxy)pyridin-2-amine (3.8 g).

Step B: Preparation of ethyl 7-(2-(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate : 4-(2-() in a round bottom flask Dimethylamino)ethoxy)pyridin-2-amine (0.87 g, 4.8 mmol) was dissolved in ethanol (15 mL). Ethyl 2-chloro-3-oxopropionate (5% benzene solution; 23 mL; solution from Toronto Research Chemicals Inc.) was added and the mixture was refluxed for 10 hours. The reaction mixture was concentrated to give a white solid (1,1 g). The solid was purified using a Biotage ruthenium dioxide column (25+) eluting with EtOAc (EtOAc) eluting Ethyl 2(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.2 g).

Step C: Preparation of 7-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indole Zin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indole Zylo-4-amine (59 mg, 0.24 mmol) was dissolved in tetrahydropyran (DriSolve; 1.2 mL) and degassed, then backfilled with nitrogen. The solution was cooled in an ice water bath for 15 minutes, followed by dropwise addition of lithium bis(trimethyldecyl)amide (0.25 mL, 1 M tetrahydrofuran). The reaction was stirred for 10 minutes and then added dropwise to ethyl 7-(2-(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (31). Mg, 0.12 mmol) in tetrahydrofuran (DriSolve; 1.2 mL). The reaction was then stirred while cooling in an ice water bath for 1.5 hours. The reaction was quenched with water and concentrated. Purification by reverse phase chromatography, eluting with a gradient of 10% to 60% ACN / water to give 7-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-(( 6-Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (30 mg). MS m/z 484.1 (M+1, APCI+).

Example 61

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidine amine

Imidazo[1,2-a]pyridine-3-carboxylic acid (62 mg, 0.38 mmol) was dissolved in sulphur chloride (112 mL, 1.5 mmol). The reaction mixture was stirred at ambient temperature for 1 hour then concentrated under high vacuum and dried 16 hr. The resulting solid was dissolved in tetrahydrofuran (2 mL). Add 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (97 mg, 0.38 mmol) and stir in a sand bath at 70 ° C 6 hours. The mixture was concentrated and partitioned between ethyl acetate and saturated sodium hydrogen sulfate. The ethyl acetate layer was washed with water and brine, then dried over sodium sulfate and evaporated. The crude material was subjected to preparative thin layer chromatography (c.c., EtOAc), eluting with 10% MeOH / DCM to afford N-(3-methyl-1-((6-methylpyridin-2-yl) )methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (48 mg), band Rf = 0.6. MS m/z 397.3 (M+1, APCI+).

Example 62

6-cyano-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-carbamamine

Step A: Preparation of ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate : 2-Amino-5-cyanopyridine (15.5 g, 152 mmol) in a 2 L round bottom flask ) Dissolved in ethanol (500 mL). Ethyl 2-chloro-3-oxopropionate (5% benzene solution; 730 mL; solution from Toronto Research Chemicals Inc.) was added and the mixture was heated under reflux for 10 hours. The mixture was concentrated under reduced pressure and purified title crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Step B: Preparation of lithium 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate: ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (13.9 g, 65 Methyl) and lithium hydroxide monohydrate (2.7 g, 65 mmol) were dissolved in tetrahydrofuran/ethanol/water (1:2:1, 150 mL: 300 mL: 150 mL). After stirring at ambient temperature for 16 hours, the solvent was removed in vacuo to give &lt;RTI ID=0.0&gt;&gt;

Step C: Dissolve lithium 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (138 mg, 0.7 mmol) in dry NMP (3.6 mL) and add 2,4,6-tris. Chlorobenzyl chloride (115 mL, 0.7 mmol). The mixture was stirred at ambient temperature for 30 minutes. Then 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (186 mg, 0.7 mmol) was added in one portion and the reaction was taken in a sand bath Heat to 80 ° C for 6 hours. Saturated sodium bicarbonate was added until a precipitate formed and was stirred at ambient temperature for 1 hour. The precipitate was filtered and dried under high vacuum for 2h to afford 6-cyano-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl) as a beige solid. 1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (140 mg). MS m/z 422.3 (M+1, APCI+).

Example 63

7-Hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine- 3-methylamine

Step A: Preparation of ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate : Dissolving 2-aminopyridin-4-ol (3 g, 27 mmol) in a 250 mL round bottom flask In ethanol (90 mL). Ethyl 2-chloro-3-oxopropionate (5% benzene solution; 130 mL; solution from Toronto Research Chemicals Inc.) was added and the mixture was refluxed for 10 hours. The reaction was concentrated and dried with EtOAc EtOAc (EtOAc)

Step B: Preparation of ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate : 7-Hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid The ester (100 mg, 0.38 mmol) was dissolved in EtOAc (EtOAc) The mixture was stirred at ambient temperature for 30 minutes, then chloromethylethyl ether (40 mg, 0.42 mmol) was then weighed and the mixture was warmed to 60 ° C for 1 hour. The crude mixture was purified by reverse phase chromatography to afford ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg).

Step C: Preparation of 7-(ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide : 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine ( 22 mg, 0.09 mmol) was dissolved in tetrahydropyran (DriSolve; 0.5 mL) and degassed, then backfilled with nitrogen. The solution was then cooled in an ice water bath for 15 minutes, followed by dropwise addition of bis(trimethyldecyl)amine lithium (0.09 mL, 1 M in tetrahydrofuran). The reaction was stirred for 10 minutes and then added dropwise to ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg, 0.04 mmol). In a solution of tetrahydrofuran (DriSolve; 0.2 mL). The reaction was then stirred while cooling in an ice water bath for 1.5 hours. The reaction was quenched with water and concentrated. The crude material obtained was purified by reverse phase chromatography eluting with a 25 column volume of 10% to 70% ACN/water gradient to afford 7-(ethoxymethoxy)-N-(3-methyl-1 -((6-Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11.2 mg).

Step D: Preparation of 7-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide : 7-(ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H- Oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11.2 mg, 0.02 mmol) was dissolved in dichloromethane (0.9 mL) . The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated and dried under high vacuum to give 7-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazole And [1,2-a]pyridine-3-carbamide (8 mg). MS m/z 413.2 (M+1, APCI+).

Example 64

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(piperazin-1-yl)ethyl Oxy)imidazo[1,2 -a]pyridine-3-carboxamide

Step A: Preparation of tert-butyl 4-fluoropyridin-2-ylaminocarbamate : Under a dry nitrogen atmosphere, the flask was charged with 2-chloro-4-fluoropyridine (20 g, 152 mmol), carbamic acid. Third butyl ester (89 g, 760 mmol), ginseng (dibenzylideneacetone) dipalladium (1.39 g, 1.52 mmol), X-PHOS (1.48 g, 3.10 mmol), cesium carbonate (99 g, 588 mmol) And tetrahydrofuran (500 mL). The mixture was refluxed under nitrogen for 7 hours. An additional 1 equivalent of cesium carbonate was added to drive the reaction to completion. The mixture was cooled to ambient temperature and filtered through celite and washed with EtOAc. The filtrate was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was washed twice with ethyl acetate. The combined organics were washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

Step B: Preparation of 4-fluoropyridin-2-amine : The flask was charged with tert-butyl 4-fluoropyridin-2-ylcarbamate (3.5 g, 16.5 mmol) and dichloromethane (100 mL). The mixture was cooled to 0-5 ° C using an ice/water bath. Trifluoroacetic acid (75 mL) was slowly added along the side of the flask with continuous stirring. The mixture was stirred overnight at ambient temperature. The mixture was concentrated and then partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc m.

Step C: Preparation of ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate : 4-fluoropyridin-2-amine (10.0 g, 48.0 mmol) in a reaction flask under dry nitrogen atmosphere Mix with ethanol (40 mL). A solution of ethyl 2-chloro-3-oxopropionate (5% benzene solution, 178 mL; solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60 ° C under nitrogen for 4 hours. After allowing the mixture to cool, the solvent was removed in vacuo to afford a brown solid. This solid was mixed with ethyl acetate (300 mL) and sodium hydrogen carbonate solution (75 mL) and dissolved with stirring. The phases were separated and the bicarbonate solution was extracted with ethyl acetate (75 mL). The combined ethyl acetate extracts were dried with sodium s The crude material was dissolved in EtOAc (EtOAc m.) ).

Step D: Preparation of 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid : ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (8 g; 44.4 mmol) Tetrahydrofuran (225 mL), ethanol (110 mL, and water (55 mL) were added. Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. The mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure to remove tetrahydrofuran. And ethanol. Hydrochloric acid (2N) was added to the aqueous mixture to adjust to pH 3. A white precipitate formed which was filtered and dried under high vacuum overnight to afford 7-fluoroimidazo[1,2 -a]pyridine-3-carboxylic acid (6.3 g).

Step E: Preparation of 7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a] Pyridine-3-carbamide : treatment of 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (0.15 g, 0.84 mmol) in anhydrous 1 with anhydrous triethylamine (0.3 mL, 2.11 mmol) A solution of -methyl-2-pyrrolidone (4 mL) was stirred until the reaction mixture became homogeneous. 2,4,6-Trichlorobenzamide chloride (0.22 g, 0.89 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 30 min. Within 5 minutes, an anhydride precipitate formed and required to be stirred vigorously. Add 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (Example 35, Step AD; 0.19 g, 0.75 mmol) in anhydrous 1- A 0.5 M solution in pyridine-2-pyrrolidone. The reaction was heated in a sand bath at 80 ° C and stirred overnight. The reaction mixture was cooled to ambient temperature and the solid was removed by filtration. The filter cake was washed with ethyl acetate and the filtrate was concentrated. The resulting material was diluted with saturated sodium bicarbonate and a dark brown precipitate formed. The precipitate was isolated by filtration to give 7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl as a brown solid. Imidazo[1,2-a]pyridine-3-carboxamide (170 mg).

Step F: Preparation of 4- (2- (3- (3-methyl-1 - ((6-methyl-pyridin-2-yl) methyl) lH-indazol-4-yl carbamoyl acyl) imidazole And [1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester : The flask was charged with solid potassium butoxide (0.07 g, 0.64 mmol), 4 -(2-Hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (0.17 g, 0.74 mmol) and tert-butanol (0.6 mL). The mixture was heated to 60 ° C for 20 minutes, followed by a one-time addition of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl) -7-Fluoroimidazo[1,2-a]pyridine-3-carboxamide (0.045 g, 0.105 mmol). The mixture was heated overnight in a sand bath at 80 ° C with stirring. The reaction mixture was quenched with water and concentrated, then purified by reverse phase chromatography on a Biotage 25+ C18 column, eluting with a 12-column volume 0-65% acetonitrile/water gradient to give a beige solid 4-(2) -(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylaminemethanyl)imidazo[1,2-a] Pyridyl-7-yloxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (40 mg). MS (APCI), positron emission scan, m/z = 639.1 (M+).

Step G: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(piperazine)-1 -yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : 4-(2-(3-(3-methyl-1-((6-methylpyridine-2)) -yl)methyl)-1H-indazol-4-ylaminecarbamimidyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (0.04 g, 0.1 mmol) was dissolved in methanol and treated with concentrated hydrogen chloride. The mixture was stirred at ambient temperature for 2 h then concentrated and dried under high vacuum overnight to afford N-(3-methyl-1-((6-methylpyridin-2-yl)methyl) as a white solid. 1H-indazol-4-yl)-7-(2-(piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (38 mg). MS (APCI), positron emission scan, m/z = 539.1 (M+).

Example 65

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-6-oxyl- 1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)pyridine-2(1H)-one : The flask was charged with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolan) ( 4.204 g, 16.56 mmol), potassium acetate (4.432 g, 45.15 mmol), DPPF (0.2502 g, 0.4515 mmol), PdCl 2 (DPPF) * dcm (0.3733 g, 0.4515 mmol) and dioxane (37 mL). The mixture was degassed with room nitrogen and stirred with stirring at 80 ° C oil bath temperature overnight. The mixture was cooled to ambient temperature and diluted with ethyl acetate and saturated sodium hydrogen sulfate. The organic layer was dried over sodium sulfate and concentrated. Purification by flash chromatography, eluting with EtOAc EtOAc EtOAc EtOAc - Dioxaborolan-2-yl)pyridine-2(1H)-one, which was solidified to a pale white solid (331 mg). MS (APCI), positron emission scan, m/z = 504.2 (M+).

Step B: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-6- Sideoxy-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide : 7-bromo-N-(3-A in 2 dram vials 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.05 g, 0.12 Ment) dissolved in dimethoxyethane: dimethylformamide (1:1, 0.8 mL) with the addition of 1-methyl-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (0.04 g, 0.17 mmol), PdCl ₂ (dppf)*dcm (0.005 g, 0.006 mmol) and 2 M carbonic acid Sodium (0.17 mL, 0.34 mmol). Nitrogen gas was bubbled through the reaction mixture over 5 minutes, then the vial was capped and heated overnight in a 90 ° C sand bath. The reaction mixture was diluted with ethyl acetate and water. A light green precipitate formed and was collected. The crude material was purified by preparative thin layer chromatography (c. s., 20×20 cm, 0.5 mm) eluting with 10% MeOH / DCM. The UV activity band with _Rf = 0.1 was separated and the cerium oxide was washed with 10% MeOH / DCM. The filtrate was concentrated to give N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl Base-6-o-oxy-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide (31 mg).

Example 66

N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole: Loading 1,4-two into the first flask Oxane/H ₂ O (30 mL/5 mL). The flask was cooled to 0 ° C and a vacuum was applied over 20 minutes. The second flask was charged with K ₂ CO ₃ (2.92 g, 21.1 mmol), 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indole Azole (1.98 g, 5.28 mmol), diethoxyphosphonium palladium (0.0592 g, 0.264 mmol), methylboronic acid (0.948 g, 15.8 mmol) and 2'-(dicyclohexylphosphino)-2,6-di Sodium methoxybiphenyl-3-sulfonate (0.270 g, 0.528 mmol). The second flask was evacuated under vacuum and backfilled N ₂ 3 times. Degassed cold dioxane/H ₂ O was then added to the second flask, which was evacuated under vacuum and backfilled with argon 5 times. The reaction mixture was heated to 80 ° C for 3 hours. The reaction was cooled to ambient temperature, filtered and concentrated EtOAc. The residue was diluted with EtOAc (200 mL). The organic layer was washed with saturated NaHCO _3, dried (Na ₂ SO ₄₎ and concentrated to give the desired product without further purification.

Step B: Preparation of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine: 1-((6-isopropylpyridine-2) -ethyl)methyl)-3-methyl-4-nitro-1H-indazole (1.51 g, 4.87 mmol) was added to a suspension of EtOH/H ₂ O (40 mL / 10 mL) (5.43) g, 97.3 mmol) and ammonium chloride (0.260 g, 4.87 mmol). The reaction mixture was heated to reflux for 3 hours, then cooled to 60 ° C and passed through celite Pad filtration. Cake was washed with _{EtOH / Et 3 N (20:} 1,200 mL) and MeOH / DCM (1: 1,100 mL ) and washed. The filtrate was concentrated and the residue was crystalljjjjjjjj The ethyl acetate was washed with NaHCO _3, dried (Na ₂ SO _4), filtered, and concentrated to give the desired product (57%).

Step C: Preparation of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-A) Isopiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: Prepared according to the method of Example 138. MS (ES+APCI) m/z = 567.1 (M+H).

Example 67

N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2 -(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

According to the method of Example 66, 1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-4-nitro-1H was used in Step B. - Preparation of carbazole in place of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole. MS (ES+APCI) m/z = 570.2 (M+H).

Example 68

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazole-4 -yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide : 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-carbazole-4- under nitrogen at ambient temperature A solution of the amine (197.8 mg, 0.784 mmol) in dry THF (3 ml) was added bis(trimethylsulfonyl)amine lithium (1.0 M in THF, 1.6 mL). The resulting mixture was stirred at ambient temperature for 10 min then added dropwise to a solution of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid methyl ester (200 mg, 0.784 mmol) in anhydrous THF (3 mL) Cold (ice water bath) solution. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and was quenched with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography on ruthenium dioxide with 8% MeOH / DCM as solvent.

Step B: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H- Pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : 1-methyl-4-(4,4) was placed in a dry flask equipped with a reflux condenser and a nitrogen line. ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.4 mg, 0.069 mmol), 7-bromo-N-(3-methyl 1-((6-Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Step AB; 30 mg, 0.063 mmol), Pd(PPh ₃ ) ₄ (3.7 mg, 0.003 mmol) and potassium carbonate (44 mg, 0.32 mmol). To the flask was added _{water: DMF: CH 3 CN (1} : 1: 4.5; 0.16: 0.16: 1.0 mL) the mixture and the reaction mixture was degassed under nitrogen, and heated to at 80 ℃ 5 hours. The reaction mixture was cooled and diluted with water. The resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute MS detected (ES+APCI) m/z = 477 (M+H).

Example 69

7-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indole Zin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

According to the procedure of Example 68, 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyridine-3-carboxamide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Preparation of 2-yl)-1H-pyrazole. ¹ H NMR (CDCl ₃ , δ) 9.55 (d, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.78 (d, 1H), 7.62 (s, 1H), 7.42 (t, 1H) , 7.34 (t, 1H), 7.15 (d, 1H), 7.06 (t, 2H), 6.52 (d, 1H), 5.64 (s, 2H), 2.87 (s, 3H), 2.58 (s, 3h), 2.40 (s, 6H).

Example 70

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1H-pyrazol-4-yl)imidazolium [1,2-a]pyridine-3-carboxamide

According to the procedure of Example 68, 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1] , 2-a]pyridine-3-carbamide and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Preparation of 1-butylic acid tert-butyl ester. MS detected (ES+APCI) m/z = 463 (M+H).

Example 71

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazole-5 -yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-carbazole : loaded into a flask equipped with a reflux condenser and a nitrogen line 3-Iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-carbazole (Example 89, Step AB; 100 mg, 0.254 mmol), tri-o-tolyl Phosphine (15.4 mg, 0.051 mmol) and ginseng (dibenzylideneacetone) dipalladium (0) (23 mg, 0.025 mmol). The flask was flushed with nitrogen and anhydrous DMF (30 mL) and &lt;RTI ID=0.0&gt;&gt;&gt; The flask was degassed under nitrogen and heated at 80 °C for 6 hours. The reaction mixture was cooled to mp. The combined organic extracts were dried over anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute

Step B: Preparation of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine: dihydroxy palladium (27 mg, 0.019 at ambient temperature) Methyl)-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (54 mg, 0.19 mmol) in anhydrous EtOH (1.5 mL) Suspension. The mixture was stirred at ambient temperature for 16 hours under a hydrogen atmosphere, followed by diatomaceous earth The pad was filtered and concentrated to give the desired desired crystallite.

Step C: Preparation of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid methyl ester: A 50 mL flask equipped with a reflux condenser and a nitrogen line was charged with 7-bromoimidazole [1,2- a] Pyridine-3-carboxylic acid (1.00 g, 4.15 mmol), DCM (20 mL), EtOAc (EtOAc: EtOAc) Four drops of DMF were added to the reaction and the flask was stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness, cooled in an ice-water bath and 30 mL MeOH was then evaporated. The reaction mixture was stirred at ambient temperature overnight, concentrated to dryness andEtOAc The suspension was extracted with EtOAc EtOAc EtOAc.

Step D: Preparation of 7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid methyl ester : to a dry flask equipped with a reflux condenser and a nitrogen line Loading 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid methyl ester (200 mg, 0.784 mmol), 1-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.869 mmol) and PdCl ₂ (dppf) dichloromethane adduct (64 mg, 0.078 mmol). To the flask was added 3 mL of 1,2-dimethoxyethane containing 1% absolute ethanol, followed by triethylamine (0.22 mL, 1.57 mmol). The flask was degassed under nitrogen and heated at 85 ° C for 10 hours. The reaction mixture was allowed to cool to ambient temperature and then diluted with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute

Step E: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H- Pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide : 3-methyl-1-((6-methylpyridine-2) at ambient temperature under nitrogen atmosphere Add bis(trimethyldecyl)amine lithium (1.0 M THF) to a solution of methyl)-1H-indazole-4-amine (46.7 mg, 0.185 mmol) in dry THF (2 mL) Solution, 0.38 mL). The resulting mixture was stirred at ambient temperature for 10 minutes and then added dropwise to methyl 7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (47.4 Mg, 0.185 mmol) in cold (ice water bath) solution in anhydrous THF (2 mL). The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and was quenched with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried over anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute MS detected (ES+APCI) m/z = 477 (M+H).

Example 72

7-(2-(Dimethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl Imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (Z)-7-(2-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-carbazole 4-yl)imidazo[1,2-a]pyridine-3-carboxamide : The flask was charged with 7-bromo-N-(3-methyl-1-((6-methylpyridine-2) -yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Step AB; 100 mg, 0.21 mmol), tri-o-tolyl Phosphine (12.8 mg, 0.042 mmol) and ginseng (dibenzylideneacetone) dipalladium (19.3 mg, 0.021 mmol). DMF (3 mL) was added to the flask followed by (Z)-tributyl(2-ethoxyvinyl)stannane (114 mg, 0.316 mmol) and triethylamine (0.04 mL, 0.30 mmol). The reaction mixture was degassed under nitrogen and stirred at 100 ° C for 10 h. The reaction mixture was cooled, diluted with H~~~~ The combined organic extracts were dried over anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute

Step B: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2- oxoethyl Imidazo[1,2-a]pyridine-3-carboxamide : (Z)-7-(2-ethoxyvinyl) treated with 45 equivalents of 4.0 M hydrochloric acid in dioxane at ambient temperature -N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-methyl A solution of decylamine (82.8 mg, 0.177 mmol) in 1:1 dioxane / water (2 mL). The reaction mixture was stirred with EtOAc EtOAc EtOAc. The combined organic extracts were dried with EtOAc EtOAc EtOAc. The crude product was used in the next step without further purification.

Step C: Preparation of 7-(2-(dimethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-carbazole 4-yl)imidazo[1,2-a]pyridine-3-carboxamide: N-(3-methyl-) is treated with an excess (10 equivalents) of sodium triethoxysulfonate at ambient temperature. 1-((6-Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-o-oxyethyl)imidazo[1,2-a]pyridine- A solution of 3-carbamide (33 mg, 0.068 mmol) and dimethylamine (0.34 mL, 0.68 mmol) in 1.4 mL 1:1 MeOH /EtOAc. The reaction mixture was stirred at ambient temperature overnight. An additional 10 equivalents of sodium triethoxysulfonate was added and stirring was continued for a further few hours. The reaction mixture was quenched with EtOAc EtOAc EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated and subjected to silicon dioxide in 8% MeOH-2% 7N NH 3 / MeOH / DCM mixtures as eluting agents preparative thin layer chromatography to thereby give 6.6 mg of the Need product. MS detected (ES+APCI) m/z = 468 (M+H).

Example 73

7-(2-Hydroxyethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide

Treatment of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4- with 3 equivalents of sodium triethoxysulfonate at ambient temperature A solution of 7-(2-oxoethyl) imidazo[1,2-a]pyridine-3-carboxamide (5 mg, 0.011 mmol) in 0.5 mL anhydrous EtOH. The reaction mixture was stirred overnight at ambient temperature before 10 equivalents of reducing agent were added. Stirring is continued until the starting material has been consumed. The reaction was quenched with EtOAc (EtOAc)EtOAc The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute MS detected (ES+APCI) m/z = 441 (M+H).

Example 74

7-(2-(2-Methoxyethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridine)- 2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

According to the procedure of Example 72, N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2- side oxygen The preparation is carried out by using ethyl)imidazo[1,2-a]pyridine-3-carboxamide and 2-methoxyethylamine. MS detected (ES+APCI) m/z = 498 (M+H).

Example 75

7-(1-(2-Hydroxyethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4 -yl)imidazo[1,2-a]pyridine-3-carboxamide

Following the procedure in Example 72, Step C, from 7-Ethyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl The imidazo[1,2-a]pyridine-3-carbamide (Example 79) and ethanolamine were prepared. MS detected (ES+APCI) m/z = 484 (M+H).

Example 76

7-(1-Hydroxyethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide

The preparation method of Example 75 was carried out as a by-product. MS detected (ES+APCI) m/z = 441 (M+H).

Example 77

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(pyrrolidin-1-yl)ethyl Imidazo[1,2-a]pyridine-3-carboxamide

According to the procedure of Example 72, from N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2- side oxygen The preparation is carried out by using phenylethyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 72, Step AB) and pyrrolidine. MS detected (ES+APCI) m/z=494 (M+H).

Example 78

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazine-1 -yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide

According to the procedure of Example 72, from N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2- side oxygen The preparation is carried out by using phenylethyl imidazo[1,2-a]pyridine-3-carboxamide and 1-methylpiperazine. The detected MS (ES+APCI) m/z = 523 (M+H).

Example 79

7-Ethyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyridine-3-carboxamide

Step A: Preparation of 7-(1-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl Imidazo[1,2-a]pyridine-3-carboxamide: A flask equipped with a reflux condenser and a nitrogen line was charged with 7-bromo-N-(3-methyl-1-((6-) Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Step AB; 74.8 mg, 0.157 mmol) Tri-o-tolylphosphine (9.6 mg, 0.031 mmol) and ginseng (dibenzylideneacetone) dipalladium (0) (14.4 mg, 0.015 mmol). Anhydrous DMF (2 mL), tributyl(1-ethoxyvinyl)tin (0.07 mL, 0.22 mmol) and triethylamine (0.03 mL, 0.22 mmol) were then taken to the flask and under nitrogen The reaction mixture was degassed and stirred at 100 ° C for 6 hours. The reaction mixture was cooled, diluted with EtOAc EtOAc. The combined organics were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by preparative EtOAc EtOAc (EtOAc)

Step B: Preparation of 7-ethenyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide: 7-(1-ethoxyvinyl)-N-(3-methyl) treated with 4.0 M HCl in dioxane (10 eq.) at ambient temperature 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (56.4 mg, 0.121 mmol ) A solution in DCM (1 mL). The reaction mixture was stirred at ambient temperature for 0.5 h then quenched with saturated aqueous sodium bicarbonate. The resulting suspension was extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium The crude product was purified by preparative EtOAc (EtOAc) elute MS detected (ES+APCI) m/z = 439 (M+H).

Example 80

N-(1-Benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-methyl Guanamine

Step A: Preparation of 3-iodo-4-nitro-1H-carbazole : Prepared according to the method of Example 89.

Step B: Preparation of 3-methyl-4-nitro-1H-carbazole : A solution of dimethylzinc (1.73 ml, 3.46 mmol) was added dropwise to 3-iodo-4-nitrol under argon. -1H-carbazole (0.500 g, 1.73 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (0.427 g, 0.519 mmol) in dioxane (0.2 M, 9 In a mixture of mL). The mixture was heated under reflux for 2 hours. After cooling, MeOH (<1 mL) was added followed by 2N HCl (1 mL) and DCM (5 mL). After the mixture was stirred for 30 minutes, the organic layer was separated, washed with saturated aqueous sodium hydrogen sulfate, water and brine. The combined organic extracts were dried (peptone-purified filter paper), concentrated and purified on EtOAc (EtOAc EtOAc EtOAc -carbazole (0.082 g, 27% yield).

Step C: Preparation of 1-benzyl-3-methyl-4-nitro -1H- indazole: 3-methyl-4-nitro -1H- indazole was cooled to 0 ℃ of (0.100 g, 0.564 Methyl hydroxide (0.0475 g, 0.847 mmol) was added to a solution of EtOAc (0.4M, EtOAc). After 15 minutes at 0 ° C, (bromomethyl)benzene (0.0737 ml, 0.621 mmol) was added. The mixture was stirred at ambient temperature overnight and then concentrated. The residue was purified on EtOAc (EtOAc EtOAcEtOAcEtOAc ).

Step D: Preparation of 1-benzyl-3-methyl-1H-indazole-4-amine : treatment of 1-benzyl-3-methyl-4-nitro- with iron (0.11 g, 1.9 mmol) A solution of 1H-carbazole (0.052 g, 0.19 mmol), ammonium chloride (0.0052 g, 0.097 mmol) in 4:1 EtOH / water (5 mL). The mixture was concentrated and the residue was crystallisjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj rate).

Step E: Preparation of N-(1-benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine -3-carboxamide : to 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.035 g, 0.148 mmol) in dichloromethane (10 mL) A mixture of dichloromethane, dichloromethane (2 M, 0.081 mL, 0.163 mmol) and catalyzed (1 drop) of DMF were added to the mixture. After stirring at ambient temperature for 30 minutes, 1-benzyl-3-methyl-1H-indazole-4-amine (0.0387 g, 0.163 mmol) (1 mL in dichloromethane) Diisopropylethylamine (0.0310 mL, 0.178 mmol). The mixture was stirred overnight and then partitioned between water and DCM. The combined organic extracts were dried (p. EtOAc EtOAc) (EtOAc) elute Methyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.022 g, 33% yield). MS (APCI) m/z = 456 (M+H).

Example 81

N-(3-Methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidine amine

Step A: Preparation of (6-methylpyridin-3-yl)methanol: Partial treatment of methyl 6-methylnicotinate (16.3 g, 108 mmol) with sodium borohydride (12.2 g, 323 mmol) at ambient temperature A solution in MeOH (150 mL). The mixture was quenched with water (100 mL) and concentrated. This mixture was diluted with water (300 mL) and EtOAc. The combined organic extracts were dried (p. EtOAc (EtOAc) EtOAc)

Step B: Preparation of 5-(chloromethyl)-2-methylpyridine hydrochloride: (6-methylpyridin-3-yl)methanol (8.54 g, 69.34 mmol) dissolved in toluene (0.5 M, 125 mL )in. Thionium chloride (10.12 mL, 138.7 mmol) was added dropwise, during which time a white solid began to precipitate from the solution. The mixture was heated to 65 ° C and stirred for 1 hour. The mixture was concentrated, EtOAc (EtOAc m.)

Step C: Preparation of 3-methyl-1-((6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole : according to the method of Example 80, using 5-(chloromethyl) The preparation of 2-methylpyridine hydrochloride in place of (bromomethyl)benzene.

Step D: Preparation of 3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazole-4-amine : according to the method of Example 80, using 3-methyl-1- ((6-Methylpyridin-3-yl)methyl)-4-nitro-1H-carbazole was prepared in place of 1-benzyl-3-methyl-4-nitro-1H-indazole.

Step E: Preparation of N-(3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine- 3-Mergamine : according to the method of Example 80, using imidazo[1,2-a]pyridine-3-carboxylic acid and 3-methyl-1-((6-methylpyridin-3-yl)methyl) -1H-carbazole-4-amine instead of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-3-methyl-1H- Preparation of oxazol-4-amine (8 mg, 11% yield). MS (APCI) m/z = 397 (M + H).

Example 82

7-(2-Methoxyethoxy)-N-(3-methyl-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide

Substituting 3-methyl-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazole-4-amine for 1-benzyl-3-yl, according to the method of Example 80 The preparation is carried out by the base-1H-carbazole-4-amine. MS (APCI) m/z = 464 (M+H).

Example 83

7-(2-Methoxyethoxy)-N-(3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide

Substituting 3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-4-amine for 1-benzyl-3-carbamate according to the method of Example 80 The preparation is carried out by the base-1H-carbazole-4-amine. MS (APCI) m/z = 464 (M+H).

Example 84

N-(1-(cyclopropylmethyl)-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine 3-carbamamine

Substituting 1-(cyclopropylmethyl)-3-methyl-1H-indazole-4-amine for 1-benzyl-3-methyl-1H-indazole-4-amine according to the method of Example 80 Preparation was carried out. MS (APCI) m/z = 420 (M+H).

Example 85

N-(3-Methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazine-1) -yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

According to the method of Example 80, 3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazole-4-amine and 7-(2-(4-methyl), respectively Substituting lithium piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate for 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine- Preparation of 3-carboxylic acid and 1-benzyl-3-methyl-1H-indazole-4-amine. MS (APCI) m/z = 539 (M+H).

Example 86

N-(1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-ethoxypicolinate : Ethyl iodide (6.90 mL, 86.3 mmol) was added to 6-hydroxypicolinic acid (3.0 g, 21.6 mmol) and silver carbonate (11.9 g, 43.1 mmol) In suspension in chloroform (0.1 M, 200 mL). The mixture was stirred at ambient temperature for 18 hours. The insoluble material was removed by filtration and washed with chloroform. The filtrate was concentrated to give ethyl 6-ethoxypyridinecarboxylate (4.14 g, 98% yield).

Step B: Preparation of (6-ethoxypyridin-2-yl)methanol : Sodium borohydride (16.0 g, 424 mmol) was added portionwise to ethyl 6-ethoxypicolinate (4.14 g, 21.2 ) over 35 min. Methyl) in EtOH solution (0.2 M, 200 mL). The resulting mixture was stirred at ambient temperature for 2 days. The mixture was concentrated and the residue was partitioned between water and DCM. The organic layer was dried (p.p. EtOAc EtOAc) EtOAc (EtOAc)

Step C: Preparation of 2-(chloromethyl)-6-ethoxypyridine hydrochloride : (6-ethoxypyridin-2-yl)methanol (3.00 g, 19.6 mmol) was dissolved in toluene (0.5 M, 40 mL). Thionylene chloride (2.86 ml, 39.2 mmol) was added dropwise, during which time a white solid began to precipitate from the solution. The mixture was heated to 65 ° C with stirring for 1 hour. The mixture was concentrated and the residue was crystallisjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Step D: Preparation of 3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro- 1H-carbazole: 3-bromo-4-nitrate at ambient temperature Potassium carbonate (1.71 g, 12.4 mmol) was added to a solution of the base-1H-carbazole (1.5 g, 6.20 mmol) in DMF (0.5 M, 12 mL). After 15 minutes, 2-(chloromethyl)-6-ethoxypyridine hydrochloride (1.29 g, 6.20 mmol) was added. The mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated and diluted with ice water (300 mL). The precipitated solid was collected by filtration, washed with water and dried under high vacuum overnight to give 3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H- Carbazole (1.21 g, 52% yield).

Step E: Preparation of 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole: at ambient temperature under argon purge Potassium carbonate (0.916 g, 6.63 mmol), methylboronic acid (0.793 g, 13.3 mmol), water (0.239 mL, 13.3 mmol), then s(triphenylphosphine)palladium(0) (0.0766 g, 0.0663 mmol) 3-Bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole (0.500 g, 1.33 mmol) in dioxane (0.2 M, 7 mL ). The mixture was refluxed overnight, cooled to mp. EtOAc (EtOAc)EtOAc. Methyl)-3-methyl-4-nitro-1H-indazole (0.118 g, 28% yield).

Step F: Preparation of 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine: Treatment with iron (0.211 g, 3.78 mmol) (6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (0.118 g, 0.378 mmol), ammonium chloride (0.0101 g, 0.189 mmol) :1 EtOH / water (2 mL) solution and reflux for 2 h. The solvent was removed and the residue was taken in EtOAc- water and filtered th The organic phase was separated, dried (phase separator polyfluorene-treated filter paper) and concentrated to give 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indole as a yellow gum. Zol-4-amine (0.076 g, 71% yield).

Step G: Preparation of N-(1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-A) Isopiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: according to the procedure of Example 85, 1-((6-ethoxypyridin-2-yl) )methyl)-3-methyl-1H-indazole-4-amine in place of 3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazole-4-amine Preparation was carried out. MS (APCI) m/z = 569 (M + H).

Example 87

N-(1-((6-methoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (6-methoxypyridin-2-yl)methanol: treatment of 6-methoxypicolinic acid (1.8 g, 11.8 mmol) of tetrahydrofuran with lithium aluminum hydride (11.8 mL, 11.8 mmol). Cold solution (0.3 M, 40 mL). The mixture was stirred at 0 °C for 30 minutes, poured into a beaker containing saturated aqueous Rochelle brine and stirring was continued at ambient temperature for 1 hour. The product was extracted with EtOAc (EtOAc) (EtOAc m.

Step B: Preparation of 2-(chloromethyl)-6-methoxypyridine hydrochloride: substituting (6-methoxypyridin-2-yl)methanol (6-ethoxypyridine) according to step 86 of Example 86 Preparation of 2-yl)methanol.

Step C: Preparation of 3-bromo-1-((6-methoxypyridin-2-yl)methyl)-4-nitro-1H-indazole: according to Example 86 Step D, using 2-(chloromethyl) Preparation of -6-methoxypyridine hydrochloride in place of 2-(chloromethyl)-6-ethoxypyridine hydrochloride.

Step D: Preparation of 1-((6-methoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole: according to Example 86, Step E, using 3-bromo-1 -((6-Methoxypyridin-2-yl)methyl)-4-nitro-1H-carbazole instead of 3-bromo-1-((6-ethoxypyridin-2-yl)methyl) Preparation of -4-nitro-1H-carbazole.

Step E: Preparation of 1-((6-methoxypyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine: 1-(6- Instead of 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl, methoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-carbazole Preparation of keto-4-nitro-1H-carbazole.

Step F: Preparation of N-(1-((6-methoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-A) Isopiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: according to Example 86, Step G, using 1-((6-methoxypyridin-2-yl) )methyl)-3-methyl-1H-indazole-4-amine in place of 1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazole-4- The amine is prepared. MS (APCI) m/z = 555 (M+H).

Example 88

N-(3-Methyl-1-((2-methylthiazol-4-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazine-1) -yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Substituting 3-methyl-1-((2-methylthiazol-4-yl)methyl)-1H-indazole-4-amine for 1-((6-B) according to the method of Example 86 Preparation of oxypyridin-2-yl)methyl)-3-methyl-1H-indazole-4-amine. MS (APCI) m/z = 545 (M + H).

Example 89

N-(3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazine-1 -yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide tetrahydrochloride

Step A: Preparation of 3-iodo-4-nitro-1H-carbazole: 4-nitro-1H-carbazole (50.0 g; 306 mmol) in DMF (600 mL) The solution was cooled to 5 °C. Powdered potassium hydroxide (68.8 g; 1226 mmol) was added. A solution of iodine (156 g; 613 mmol) in DMF (200 mL) was slowly added to the reaction mixture over 2 h while maintaining a temperature between 5 and 10 °C. The mixture was stirred at 25 ° C for 24 hours. Additional iodine (39.0 g; 153.2 mmol) and potassium hydroxide (17.2 g; 306.5 mmol) were added. The mixture was further stirred at 25 ° C for 12 hours. The reaction mixture was added to aqueous sodium hydrogensulfite (10% solution; 3300 mL) with stirring. The resulting precipitate was collected by filtration and washed with water. The material was dried in a vacuum oven at 40 °C. This material was dissolved in dichloromethane/methanol (10:1; 1.5 L) via celite Filter to remove inorganic impurities. The solution was concentrated under vacuum to give 3-iodo-4-nitro-1H-carbazole (75 g) as a yellow solid.

Step B: Preparation of 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-carbazole : 3-iodine under stirring in a dry nitrogen atmosphere 2-(Bromomethyl)-6-methylpyridine (122 mg, 0.656 mmol) was added to a solution of -4-nitro-1H-indazole (172 mg, 0.596 mmol) in anhydrous DMF (3 mL) Potassium carbonate (165 mg, 1.19 mmol). The mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with water (20 mL) and EtOAc evaporated. The organic phase was combined, washed with aq. The material obtained was purified by preparative cerium oxide chromatography eluting with hexane/ethyl acetate (3:1) to give 3-iodo-1-((6-methylpyridin-2-yl)methyl) 4-Nitro-1H-carbazole (213 mg).

Step C: Preparation of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-carbazole : in a dry flask equipped with a reflux condenser and a nitrogen line 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (100 mg, 0.254 mmol), tri-o-tolylphosphine (15.4 mg, 0.051 mmol) and ginseng (dibenzylideneacetone) dipalladium (0) (23 mg, 0.025 mmol). The flask was flushed with aq. EtOAc (3 mL) and EtOAc (EtOAc) The flask was degassed under nitrogen and heated at 80 °C for 6 hours. The reaction mixture was cooled to ambient temperature, diluted with H~~~~ The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute

Step D: Preparation of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4-amine : 10% palladium hydroxide on carbon at ambient temperature ( 27 mg, 0.019 mmol) of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (54 mg, 0.19 mmol) in anhydrous EtOH Suspension in 1.5 mL). The mixture was stirred at ambient temperature for 16 hours under a hydrogen atmosphere, and then passed through diatomaceous earth. The pad was filtered and washed with EtOH. The filtrate was concentrated under reduced pressure to give crystals (yel.

Step E: Preparation of N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methyl) piperazin-1-yl) ethoxy) imidazo [1,2-a] pyridine-3-acyl-amine tetrahydrochloride: to a solution, under vigorous stirring, for 3 minutes 3-methyl - 1-((6-Methylpyridin-2-yl)methyl)-1H-indazole-4-amine (1.67 g; 6.62 mmol) in cold (0 ° C) solution in anhydrous THF (10 mL) Lithium bis(trimethyldecyl)amine (6.50 mL; 1.0 M in THF; 6.50 mmol) was added dropwise. The reaction mixture was stirred while cooling with ice/water for 10 minutes. Ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate was added dropwise via syringe over 8 minutes (Preparation A ; 1.00 g; 3.01 mmol) in anhydrous THF (10 mL), and rinsed with THF (1 mL). The mixture was stirred in an ice/water bath for 30 minutes. The mixture was quenched with water (50 mL) and saturated aqueous ammonium chloride (50 mL). The mixture was extracted with DCM (150 mL). Aqueous brine was added to the aqueous phase (150 mL) and then extracted with DCM (100 mL). The pH of the aqueous phase was then adjusted to pH 10-11 with 2N NaOH solution. The aqueous layer was then extracted with DCM (50 mL) and ethyl acetate (50 mL). The combined organic phases were washed with brine (100 mL). The brine solution was back extracted with DCM (25 mL). The combined organic layers were dried with sodium s The residue was purified by EtOAc EtOAc EtOAc (EtOAc) The material was then precipitated from a very small volume of DCM (cooled to 4 ° C to precipitate) to afford a pale yellow solid which was dried under vacuum at <RTI ID=0.0>38 </RTI><RTIgt; This material (1.05 g) was dissolved in methanol and excess HCl (2 M ether) was added. The solvent was removed in vacuo and dried under high vacuum for 16 h to afford N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-carbazole as an off white solid. 4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide tetrahydrochloride (1.20 g ). _{^{1 H NMR CD 3 OD 9.61 (}} d, 1H), 8.81 (s, 1H), 8.34 (t, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.54 (m, 2H), 7.44 ( Dd,1H), 7.32(d,1H), 7.25(d,1H), 5.97(s,2H),4.81(t,2H),3.91(t,2H),3.81(bs,8H),3.04(s , 3H), 2.87 (s, 3H), 2.61 (s, 3H).

Example 90

N-(1-Benzyl-1H-indazol-4-yl)-7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidine amine

Step A: Preparation of 4-(2-(N-morpholinyl)ethoxy)pyridin-2-amine : Treatment of 2-(N-morpholinyl)ethanol (2.21 g, with sodium (0.407 g, 17.7 mmol) 16.8 mmol) until a homogeneous suspension is obtained. 4-Chloropyridin-2-amine (1.14 g, 8.86 mmol) was added and the mixture was heated at 145 ° C for 10 hours with stirring under magnetic stirring. The reaction mixture was cooled and diluted with water and EtOAc. The layers were separated and the aqueous extracted twice with EtOAc. The combined organic extracts were concentrated to give EtOAc (EtOAc m.

Step B: Preparation of ethyl 7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate : 4-(2-(N-morpholinyl) Ethoxy)pyridin-2-amine (1.37 g, 6.14 mmol) was dissolved in EtOAc (20 mL) andEtOAcEtOAcEtOAc . The mixture was refluxed overnight. The reaction mixture was cooled with EtOAc EtOAc EtOAc m. 1.0 g of the desired product was obtained as a white solid.

Step C: Preparation of 7-(2-(N-morpholinyl)ethoxylate of 7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate ) imidazo [1,2-a] pyridine-3-carboxylic acid: ethyl 7- (2- (N- morpholino) ethoxy) imidazo [1,2-a] pyridine-3-acetic acid The ester 4-(2-(N-morpholinyl)ethoxy)pyridin-2-amine (1.0 g, 3.13 mmol) was dissolved in a 4:1 THF/water mixture (to a concentration of 0.5 M). Lithium hydroxide monohydrate (75 mg, 3.13 mmol) was added and the resulting mixture was stirred overnight at ambient temperature then heated at 65 °C for 8 hours. An additional 0.1 equivalent of lithium hydroxide monohydrate was added and heating was continued overnight at 65 °C. The reaction mixture was diluted with EtOAc EtOAc m.

Step D: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine- 3-Mercaptoamine: suspension of lithium 7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (42 mg, 0.142 mmol) in DCM Grass chloroform (1.1 equivalents) and 1 drop of DMF were added to the solution. The mixture was stirred until the evolution of gas was stopped. 1-Benzyl-1H-indazol-4-amine (31.6 mg, 0.142 mmol) and Hunig's base (1.2 eq.) were then added to the reaction mixture. The reaction was stirred at ambient temperature for 2 hours and then concentrated. The residue was triturated with EtOAc (EtOAc)EtOAc. MS detected (ES+APCI) m/z = 497 (M+H).

Example 91

N-(1-Benzyl-1H-indazol-4-yl)-7-(2,3-dihydroxypropoxy)imidazo[1,2-a]pyridine-3-carboxamide

Treatment of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazole with oxalic acid chloride (1.1 eq.) and 1 drop of DMF at ambient temperature [1,2-a]pyridine-3-carboxylic acid (Example 58, Step AC; 109.7 mg, 0.375 mmol) in DCM. After the evolution of the gas was stopped, 1-benzyl-1H-indazole-4-amine (83.8 mg, 0.375 mmol) and Hunig's base (1.2 eq.) were added and stirring was continued overnight. The mixture was concentrated and triturated with diethyl ether then purified eluting with EtOAc EtOAc EtOAc MS detected (ES+APCI) m/z = 458 (M+H).

Example 92

N-(1-Benzyl-1H-indazol-4-yl)-7-hydroxyimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate : To potassium 2-chloro-3-ethoxy-3-oxopropan-1-en-1-carboxylate (16.4 g, 86.3 mmol) 2-Aminopyridin-4-ol (3 g, 27 mmol) was added to a cold (0 ° C) solution of concentrated sulfuric acid (43.5 mmol) and ethanol (50 mL). The resulting mixture was allowed to warm to ambient temperature and refluxed for 10 h. The reaction was concentrated and suspended in EtOAc. The solid was isolated to give 829 mg of pure product. The supernatant was concentrated and chromatographed on EtOAc (EtOAc) elute

Step B: Preparation of 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid : treatment of 7-hydroxyimidazo[1,2-a with lithium hydroxide monohydrate (2.1 equivalents) at ambient temperature a solution of pyridine-3-carboxylate (414 mg, 2.01 mmol) in 2:1:1 THF/EtOAc/water mixture (36 mL). The reaction mixture was stirred at ambient temperature overnight. An additional 2.1 equivalents of lithium hydroxide monohydrate was then added to the reaction and stirring was continued for 72 hours. After removing the volatiles, the mixture was diluted with water, cooled in an ice-bath and adjusted to pH 4 with 6 N aqueous hydrochloric acid. The resulting white precipitate was separated and dried to give the desired product (358 mg).

Step C: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-hydroxyimidazo[1,2-a]pyridine-3-carboxamide: EDCI at ambient temperature (192 mg, 0.679 mmol), 2,4,6-trimethylpyridine (224 mg, 1.85 mmol) and 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid (110 mg, 0.617 mmol) The suspension in DMF (2 mL) was stirred for 2 h. A solution of 1-benzyl-1H-indazole-4-amine (138 mg, 0.617 mmol) in DMF (2 mL). The heterogeneous mixture was stirred overnight at ambient temperature then diluted with EtOAc and washed twice with 1M aqueous HCI then brine. The organic layer was concentrated and chromatographed on EtOAc (EtOAc:EtOAc) MS detected (ES+APCI) m/z = 384 (M+H).

real Example 93

3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl) Methyl benzoate

Step A: Preparation of methyl 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate : to 3-iodo-4-nitro-1H-carbazole (1.0 2-tert-butyl-1,1,3 was added dropwise to a slurry of g, 3.46 mmol) and methyl 3-(bromomethyl)benzoate (1.59 g, 6.92 mmol) and CH ₃ CN (12 mL) 3-Tetramethylhydrazine (0.697 mL, 3.46 mmol) and the mixture was stirred at ambient temperature overnight. The mixture was then concentrated and diluted with saturated aqueous NH ₄ Cl (40 mL) and EtOAc (70 mL). The organic layer was separated and EtOAc (EtOAc) The combined organic extracts were washed with brine, then dried over Na ₂ SO _4, filtered and concentrated. The crude product was purified by EtOAc EtOAc EtOAc EtOAc

Step B: Preparation of methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate : 3-((3-iodo-4-nitro-1H-indazole-1) A suspension of methyl-methyl)benzoate (1.00 g, 2.29 mmol) and MeOH (45 mL) was cooled to 0 °C. Zinc dust (0.748 g, 11.4 mmol), followed by the addition of saturated aqueous NH ₄ Cl (23 mL). The mixture was stirred at 0 °C for 2 hours, then warmed to ambient temperature and stirred for additional 3 hours. The mixture was diluted with MeOH and filtered. Saturated aq NH ₄ OAc was added to the filtrate and the mixture was concentrated to remove the large amount of MeOH. The mixture was concentrated and extracted with EtOAc and washed the combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine, then dried over Na ₂ SO _4, filtered and concentrated. The product was purified by EtOAc EtOAc (EtOAc)

Step C: Preparation of 3-((4-(7-(2-methoxyethoxy))imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl Methyl)benzoic acid methyl ester: 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.260 g, 1.05 mmol) and NMP (3.5) were added to the vial. mL). Triethylamine (0.243 mL, 1.74 mmol) was added and the mixture was stirred until homogeneous. 2,4,6-Trichlorobenzamide chloride (0.153 mL, 0.975 mmol) was added and the mixture was stirred at ambient temperature for 0.5 h. Add a solution of methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.196 g, 0.697 mmol) in NMP (1.2 mL) and seal the reaction mixture in a vial and The temperature was raised to 80 ° C overnight with stirring. The reaction mixture was cooled and diluted with EtOAc (20 mL) and then filtered to remove white solid. The solid was washed with EtOAc and the filtrate was concentrated in vacuo. Washed with water / saturated aqueous NaHCO ₃ (25 mL, 1: 1) solution to dilute the concentrate, a precipitate formed. The precipitate was isolated by filtration and the solid was washed with water, Et ₂ O and hexanes, then dried in vacuo at 40 ℃ 4 hours to obtain 0.279 g (74%) of the title compound. MS (ES+APCI) m/z = 500 (M+H).

Example 94

N-(1-(3-Aminomethylbenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine- 3-methylamine

Add 3-((4-(7-(2-methoxyethoxy))imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl to the vial Methyl)benzoic acid (0.020 g, 0.0412 mmol), HOBT (0.00612 g, 0.0453 mmol) and EDCI (0.00869 g, 0.0453 mmol) followed by THF (0.500 mL). Diisopropylethylamine (0.00789 mL, 0.0453 mmol) was added and the mixture was stirred for 15 min. Ammonium carbonate (0.0119 g, 0.124 mmol) was added in one portion and the mixture was stirred vigorously overnight. The mixture was diluted with water, and the resulting precipitate was separated by vacuum filtration and washed with water. The solid was isolated and slurried in Et ₂ O and filtered, and the solid was washed with Et ₂ O and hexanes, then dried in vacuo (0.025 g). By prep _{TLC (10% MeOH / CH 2} Cl 2) Purification of the crude solid to give 0.003 g (15%) of the desired product. MS (ES+APCI) m/z = 485 (M+H).

Example 95

7-(2-methoxyethoxy)-N-(1-(3-(methylaminomethyl)benzyl)-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide

Add 3-((4-(7-(2-methoxyethoxy))imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl to the vial Methyl)benzoic acid methyl ester (Example 93; 0.026 g, 0.0521 mmol), followed by the addition of methylamine (0.972 mL, 7.81 mmol, 33% EtOH solution), and the mixture was sealed and heated to 50 ° C with stirring. It lasted 8 hours. Additional methylamine (0.972 mL, 7.81 mmol) was added and the mixture was stirred at 50 ° C overnight. The mixture was cooled to ambient temperature and purified directly by prep _{TLC (10% MeOH / CH 2} Cl 2), to give 0.014 g (54%) product as a pale brown powder. MS (ES+APCI) m/z = 499 (M+H).

Example 96

3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indole Methyl oxazol-1-yl)methyl)benzoate dihydrochloride

Step A: Preparation of methyl 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate : to 3-iodo-4-nitro-1H-carbazole (1.0 2-tert-butyl-1,1,3 was added dropwise to a slurry of g, 3.46 mmol) and methyl 3-(bromomethyl)benzoate (1.59 g, 6.92 mmol) and CH ₃ CN (12 mL) , 3-tetramethylguanidine (0.697 mL, 3.46 mmol), and the mixture was stirred at ambient temperature overnight. The mixture was concentrated and diluted with saturated aqueous NH ₄ Cl (40 mL) and EtOAc (70 mL). The layers were combined and separated and the aqueous extracted with EtOAc EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO _4, filtered and concentrated. The crude product was purified by EtOAc EtOAc EtOAc EtOAc

Step B: Preparation of methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate: 3-((3-iodo-4-nitro-1H-indazole-1) A suspension of methyl-methyl)benzoate (1.00 g, 2.29 mmol) and MeOH (45 mL) was cooled to 0 °C. Zinc dust (0.748 g, 11.4 mmol), followed by the addition of saturated aqueous NH ₄ Cl (23 mL). The mixture was stirred at 0 °C for 2 hours and then warmed to ambient temperature with stirring for 3 hours. The mixture was diluted with MeOH and filtered. Saturated aq NH ₄ OAc was added to the filtrate and the mixture was concentrated to remove the large amount of MeOH. Mixture was extracted with EtOAc, and the combined organic extracts were _washed with saturated aqueous NaHC03 followed by brine, dried over Na ₂ SO _4, filtered and concentrated. The product was purified by EtOAc EtOAc (EtOAc)

Step C: preparation of 3 - ((4- (7- (2- (4-methylpiperazin-1-yl) ethoxy) imidazo [1,2-a] pyridine-3-acyl group -1H-carbazol-1-yl)methyl)benzoic acid methyl ester dihydrochloride: 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1, A mixture of 2-a]pyridine-3-carboxylic acid lithium (0.09578 g, 0.2933 mmol) and NMP (1.5 mL) was warmed to give a homogeneous solution and then cooled to ambient. 2,4,6-Trichlorobenzamide chloride (0.04277 mL, 0.2737 mmol) was added and the mixture was stirred at ambient temperature for 0.5 h. Add a solution of methyl 3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.055 g, 0.1955 mmol) in NMP (1.5 mL), and warm the mixture to &lt; 4 hours. The mixture was dissolved in MeOH and concentrated. The residue was dissolved in saturated aqueous NaHCO ₃ and EtOAc, and the organic layer was washed with brine and dried over Na ₂ SO _4. By column chromatography (supplemented with 1% 7 N NH ₃ / MeOH of _{15% MeOH / CH 2 Cl 2} ) The crude material was purified to give the free base form of 3 - ((4- (7- (2- ( Methyl 4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate . This material was dissolved in MeOH (3.0 mL) and CHCl ₃ (1.0 mL) and add HCl (1.955 mL, 3.910 mmol, 2.0 MEt 2 O) and the mixture was stirred for 2 hours, and then concentrated. The resulting solid was washed with hexane and then dried with a vacuum and with Et ₂ O, to give 0.085 g (64%) of the title compound. MS (ES+APCI) m/z = 568 (M+H-2HCl).

Example 97

N-(1-(3-(Dimethylaminomethane)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)B Oxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Step A: Preparation of 3-(chloromethyl)-N,N-dimethylbenzamide : dimethylamine (2.91 mL, 5.82 mmol, 2.0 M THF), NEt ₃ (0.885 mL, 6.35 mmol) The solution of CH ₂ Cl ₂ 30 mL was cooled to 0 °C. Was added 3- (chloromethyl) benzoyl chloride (1.0 g, 5.29 mmol) of CH ₂ Cl ₂ solution (3 mL) and the solution was stirred for 2 hours at 0 ℃, and then stirred at ambient temperature for 2 hours. , And dried with 1N HCl followed by brine The organic layer was dried reactant Na ₂ SO _4, filtered and concentrated. The product was purified by column chromatography (EtOAc) eluting

Step B: Preparation of 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide : Addition of 3-iodo to the flask 4-Nitro-1H-carbazole (0.500 g, 1.73 mmol) and CH ₃ CN (6 mL) followed by 2-t-butyl-1,1,3,3-tetramethylhydrazine (0.523 ml, 2.59 mmol). The mixture was stirred for 5 minutes, and then added 3- (chloromethyl) -N, N- dimethyl-benzoyl amine (0.479 g, 2.42 mmol) of CH ₃ CN (4 mL) was added. The reaction was stirred at ambient temperature for 5 hours. The mixture was concentrated and diluted with saturated aqueous NH ₄ Cl (20 mL) and EtOAc (60 mL). The layers were mixed and separated and the organic phase was washed with brine, dried over Na ₂ SO ₄ will, filtered and concentrated. The crude product was purified by column chromatography (EtOAc) eluting

Step C: Preparation of 3-((4-Amino-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide : 3-((3-iodo-4-nitrate) A solution of yl-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide (0.400 g, 0.888 mmol) and MeOH (8.8 mL) was cooled to 0. Zinc powder (0.290 g, 4.44 mmol) was added, and the mixture was stirred vigorously for 15 minutes, then a saturated aqueous solution of NH ₄ Cl (9 mL) was added dropwise. The mixture was vigorously stirred at 0 ° C for 15 minutes and then warmed to ambient temperature and stirred for an additional 1 hour. The mixture was diluted with MeOH and filtered. Saturated aq NH ₄ OAc was added to the filtrate and the mixture was concentrated to remove the large amount of MeOH. The mixture was extracted with EtOAc and washed the combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO _4, filtered and concentrated. By column chromatography (2 to 20% IPA / CHCl ₃₎ The crude product was purified to give 0.160 g (61%) as a yellow / orange solid of the title compound.

Step D: Preparation of N-(1-(3-(dimethylaminocarbamimidyl)benzyl)-1H-indazol -4-yl)-7-(2-(4-methylpiperazine-1 -yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride: 3-((4-Amino-1H-carbazole-1) in an ice/brine bath a solution of methyl-methyl)-N,N-dimethylbenzamide (0.15 g, 0.51 mmol) and THF (1.0 mL) was cooled to -5 °C then LHMDS (0.48 ml, 0.48 mmol) , 1.0 M THF solution) and the mixture was stirred for 10 minutes, during which time a dark emulsion formed. Ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (preparation A; 0.080 g, 0.24 mmol) THF solution (1.0 mL). The reaction was stirred at -5 to 0 ℃ 1 h, then quenched with saturated aqueous NH ₄ Cl (10 mL). The mixture was extracted with CH ₂ Cl ₂ and the combined organic layers were washed with brine, dried over Na ₂ SO _4, filtered and concentrated. Under vigorous stirring, in the Et ₂ O in the crude residue was slurried and then filtered through nylon screening procedures, to give a crude product, purity> 90% (0.083 g). By column chromatography (using 5% NH ₄ OH / 5 to 20% MeOH MeOH sum / CH ₂ Cl ₂₎ Purification of the crude product. Fractions were concentrated and the product was dissolved in CH ₂ Cl ₂ and subsequently filtered. The filtrate was concentrated to give N-(1-(3-(dimethylaminocarbamoyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methyl) as a pale orange solid. Piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.060 g). This product was dissolved in MeOH (2.4 mL) and subsequently added HCl (2.41 mL, 4.81 mmol, 2.0 M Et 2 O solution). The mixture was stirred for 2 hours and then concentrated. The resulting solid was dried in vacuo and washed with Et ₂ O and hexane, to give 0.050 g (31%) of the title product as a beige powder. MS (ES+APCI) m/z = 581 (M+H-2HCl).

Example 98

7-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-(3-(trifluoromethyl)benzene) -1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Step A: Preparation of 3-iodo-4-nitro-1-(3-(trifluoromethyl)benzyl)-1H-carbazole: 3-iodo-4-nitro-1H-carbazole (0.410) g, 1.42 mmol) was added and the CH ₃ CN (7.0 mL) slurry of 1- (bromomethyl) -3- (trifluoromethyl) benzene (0.261 mL, 1.70 mmol) and the solution was cooled to 0 ℃. 2-Terbutyl-1,1,3,3-tetramethylguanidine (0.372 mL, 1.84 mmol) was added and the mixture was gradually warmed to ambient temperature and stirred at this temperature for 2 hr. The mixture was concentrated and diluted with saturated aqueous NH ₄ Cl (20 mL) and EtOAc (75 mL). The layers were separated and mixed, and the organic phase was washed with brine, dried over Na ₂ SO ₄ will, filtered and concentrated. The crude product was taken up in EtOAc (EtOAc) elute

Step B: Preparation of 1-(3-(trifluoromethyl)benzyl)-1H-indazole-4-amine: Add 3-iodo-4-nitro-1-(3-( ) to a round bottom flask Trifluoromethyl)benzyl)-1H-indazole (0.540 g, 1.21 mmol) and MeOH (12 mL). Zinc dust (0.395 g, 6.04 mmol), followed by the addition of saturated aqueous NH ₄ Cl (12 mL). The mixture was vigorously stirred at ambient temperature for 2 hours. The reaction mixture was filtered and washed with EtOAc EtOAc. Saturated aq NH ₄ OAc (25 mL) was added to the filtrate and the mixture was concentrated to remove the organic solvent. The aqueous phase was then extracted with EtOAc (3×20 mL). The drying of the combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine over Na ₂ SO _4, filtered and concentrated. By using 5% MeOH / CH ₂ Cl ₂ of 1 mm preparative TLC purification of the crude residue to give 0.120 g (34%) dark yellow / orange oil.

Step C: Preparation of 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(3-(trifluoromethyl)benzyl)-1H-indazole- 4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride : 1-(3-(trifluoromethyl)benzyl)-1H- in an ice/salt bath A solution of oxazol-4-amine (0.053 g, 0.18 mmol) in THF (1.1 mL) was cooled to -10. LiHMDS (0.19 mL, 0.19 mmol, 1.0 M THF) was added and the mixture was stirred 15 min. To this dark solution was added ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation A; 0.030 g , 0.090 mmol) in THF (1.1 mL). The mixture was slowly warmed to 0 ° C and stirred at this temperature for 3 hours. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted with CHCl _3. Dried combined organic layers were washed with brine Na ₂ SO _4, filtered and concentrated. By prep TLC (1 mm, plus 1% NH ₃ of _{10% MeOH / CH 2 Cl 2} (7N MeOH) Purification of the crude product was a pale brown solid 0.026g of the free base form of the title compound in Et ₂ O the solids in the slurry was prepared and filtered, and the solid was washed with Et ₂ O and hexane. this material was dissolved in MeOH (2.0 mL) and add HCl (0.90 mL, 1.8 mmol, 2.0 M Et 2 O solution) . the solution was stirred for 2 hours to form a white suspension. the mixture was filtered through a polypropylene screening procedures to separate a solid. the solid was washed with Et ₂ O followed by hexane, and dried in vacuo to give 0.026 g (44%) off-white solid title Compound (MS+APCI) m/z = 578 (M+H-2HCl).

Example 99

N-(1-(3-Cyanobenzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1- Ethyl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzonitrile. According to the method of Example 104, 3-(bromomethyl)benzonitrile The preparation was carried out instead of 3-(bromomethyl)-1-methylpyridine-2(1H)-one.

Step B: Preparation of 3-((4-amino-1H-indazol-1-yl)methyl)benzonitrile. 3-((3-Iodo-4-nitro-1H-carbazole-1- The slurry of methyl)benzonitrile (0.200 g, 0.495 mmol) and MeOH (10.0 mL) was cooled to 0 ° C, followed by the addition of zinc powder (0.162 g, 2.47 mmol) and saturated aqueous NH ₄ Cl (10 mL) ). The mixture was stirred at 0 °C for 1 hour, then warmed to ambient temperature and stirred overnight. The mixture was diluted with MeOH and filtered. The solid was washed with CH ₂ Cl ₂ and MeOH. Saturated aq NH ₄ OAc was added to the filtrate and the mixture was concentrated to remove the large amount of MeOH. The mixture was then extracted with EtOAc, washing of the combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO _4, filtered and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc)

Step C: Preparation of N-(1-(3-cyanobenzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy) Imidazo[1,2-a]pyridine-3-carboxamide. Add 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a to the vial. Lithium pyridine-3-carboxylate (0.187 g, 0.544 mmol) and NMP (3.0 mL), and the mixture was warmed until homogeneous and then cooled to ambient. 2,4,6-Trichlorobenzamide chloride (0.0793 mL, 0.507 mmol) was added and the dark solution was stirred at ambient temperature for 0.5 h. Add 3-((4-Amino-1H-indazol-1-yl)methyl)benzonitrile (0.090 g, 0.362 mmol) in NMP (3.0 mL) and warm the mixture to 75 ° C with stirring It lasted 3 hours. The reaction was allowed to equilibrate to ambient temperature and and saturated aqueous NaHCO ₃ (10 mL) mixture was diluted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated by column chromatography (adding _{1% 7N NH 3/15%} MeOH MeOH sum / CH ₂ Cl ₂₎ was purified. Et ₂ O will be formed in a red / brown solid and the slurry was then filtered, and the isolated solid was washed with Et ₂ O, to give a pale red / brown solid, which was dried in vacuo to give 0.095 g (42%) of the desired product. MS (ES+APCI) m/z = 535 (M+H).

Example 100

N-(5-Chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl) Ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazole-4-amine. 1-(3-(Trifluoromethyl)benzene under N ₂ A solution of methyl)-1H-indazole-4-amine (0.056 g, 0.192 mmol) in THF (1.0 mL) was cooled to -78. H ₂ SO ₄ (0.00512 mL, 0.0961 mmol) was added and the mixture was stirred for 5 min. N-chlorosuccinimide (0.0257 g, 0.192 mmol) was added in one portion and the reaction was stirred at -78 ° C for 1 hour. Sodium carbonate (0.0204 g, 0.192 mmol) was added and the mixture was allowed to warm to ambient. The mixture was diluted with water (5 mL) andEtOAcEtOAc The combined organic layers were washed with brine and dried over Na ₂ CH ₄ The crude product was purified by preparative TLC (40%EtOAc / hexanes). The higher band was identified as the title compound (0.028 g, 44%) and isolated as a dark yellow/green solid.

Step B: Preparation of N-(5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: 5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-carbazole A solution of the 4-amine (0.024 g, 0.074 mmol) in THF (0.750 mL) was cooled to -10 &lt;RTI ID=0.0&gt;&gt; The mixture was stirred for 15 minutes and ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate was added (Preparation A; 0.049 g , 0.15 mmol) in THF (0.750 mL). The mixture was slowly warmed to 0 ° C and stirred at this temperature for 3 hours. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted with CH _{2 2} Cl. The combined organic extracts were washed with brine and dried over Na ₂ SO _4, filtered and concentrated. By prep TLC (1 mm, containing 1% NH ₃ of _{10% MeOH / CH 2 Cl 2} (7 N MeOH)) Purification of the crude product. In Et ₂ O in the resulting solid was slurried and filtered, and washed with Et ₂ O and then finally the solid was washed with hexane to give the title compound as a pale brown powder (0.002 g, 4%). MS (ES+APCI) m/z = 612 (M).

Example 101

N-(7-Chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1- Ethyl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride

Step A: Preparation of 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine : 3-iodo-1-((6-methylpyridin-2-yl) A solution of methyl)-4-nitro-1H-indazole (1.00 g, 2.54 mmol) in MeOH (25 mL) was cooled to 0. Zinc powder (0.829 g, 12.7 mmol) was added and the mixture was stirred for 10 minutes. Saturated aqueous NH ₄ Cl (25 mL) and vigorously stirred mixture for 2 hours at 0 ℃, then warmed to ambient temperature and stirred for 2 hours. Then saturated aqueous NH ₄ Cl (12.5 mL) and the mixture was further stirred for 2 hours at ambient temperature. The mixture was diluted with MeOH and filtered. Saturated aq NH ₄ OAc was added to the filtrate and the mixture was concentrated to remove the large amount of MeOH. Dried mixture was extracted with EtOAc and the combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine over Na ₂ SO _4, filtered and concentrated. By column chromatography (2 to 20% IPA / CHCl ₃₎ The product was purified to give 0.428 g (70%) product as an orange solid.

Step B: Preparation of 7-chloro-1 - ((6-methyl-pyridin-2-yl) methyl) lH-indazol-4-amine: Under a N ₂ l - ((6-methyl-pyridin - A solution of 2-yl)methyl)-1H-indazole-4-amine (0.390 g, 1.64 mmol) and THF (8.0 mL) was cooled to -78. H ₂ SO ₄ (0.0436 mL, 0.818 mmol) was added and the obtained brown suspension was stirred for 5 min. N-chlorosuccinimide (0.219 g, 1.64 mmol) was added in one portion and the reaction was stirred at -78 ° C for 1 hour. Sodium carbonate (0.173 g, 1.64 mmol) was added and the mixture was allowed to warm to ambient. The mixture was diluted with water (20 mL) and EtOAc. Combined organic layers were washed with brine and dried over Na ₂ SO _4, filtered and concentrated. The crude product was purified by column chromatography (5 to 30% EtOH /hexane). The desired product was found in the lower band from the column but was contaminated with amber iodide, so the product was dissolved in 0.5 N HCl and extracted with CHCl3. The aqueous phase was basified with NaHCO3 and extracted with EtOAc. , EtOAc was washed with brine and dried over Na ₂ SO _4, filtered, and concentrated to give the title compound as a pale orange solid (0.150 g, 33%).

Step C: Preparation of N-(7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperidine) Pyrazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride: containing 7-(2-(4-methylpiperazin-1-yl) A vial of ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.171 g, 0.550 mmol) and NMP (3.0 mL) was warmed to provide a homogeneous solution and then cooled to ambient. 2,4,6-Trichlorobenzamide chloride (0.0803 mL, 0.513 mmol) was added and the dark solution was stirred at ambient temperature for 0.5 h. Add a solution of 7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.100 g, 0.367 mmol) in NMP (3.0 mL) with stirring The mixture was heated to 80 ° C overnight. The reaction was allowed to equilibrate to ambient temperature and and saturated aqueous NaHCO ₃ (10 mL) mixture was diluted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na ₂ SO _4, filtered and concentrated. By column chromatography (adding 1% 7 N NH ₃ / MeOH of 15% IPA / CHCl ₃₎ The crude product was purified to give N- (7- chloro-1 - ((6-methyl-pyridin-2-yl )methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-methyl Guanamine. This product was dissolved in MeOH (4.0 mL) and CH ₂ Cl ₂ (1.0 mL) and add HCl (3.67 mL, 7.33 mmol, 2.0 M Et 2 O solution). The mixture was stirred for 2 hours and then concentrated. The resulting solid was then dried and finally Et ₂ O and washed with hexane under vacuum overnight, to give 0.140 g (50%) of the title compound. MS (ES+APCI) m/z = 559 (M+H-3HCl).

Example 102

7-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1 ,2-a]pyridine-3-carbendamine trihydrochloride

Step A: Preparation of 3-iodo-4-nitro-1-(pyridin-3-ylmethyl)-1H-carbazole : Add 3-iodo-4-nitro-1H-carbazole to the flask (0.300 g , 1.04 mmol) and 4- (bromomethyl) pyridine hydrobromide (0.315 g, 1.25 mmol) in CH (5.0 mL) in the slurry was ₃ CN. 2-Terbutyl-1,1,3,3-tetramethylguanidine (0.460 mL, 2.28 mmol) was added and the mixture was stirred overnight. The mixture was diluted with water (20 mL) and stirred for 15 min and filtered. Collected solid was washed with water and then washed with Et ₂ O and hexane, and dried in vacuo to give the title compound as a tan powder (0.304 g, 71%), which was used directly in the subsequent step.

Step B: Preparation of 1-(pyridin-3-ylmethyl)-1H-indazole-4-amine : to 3-iodo-4-nitro-1-(pyridin-3-ylmethyl)-1H- A vial of carbazole (0.145 g, 0.381 mmol) was added THF (2.4 mL) and MeOH (1. To this solution was added zinc powder (0.249 g, 3.81 mmol) followed by HCl (2.54 mL, 7.63 mmol, 3.0 M aqueous). The mixture was stirred for 1.0 hour. The mixture was filtered through GF/F filter paper and the collected solid was washed with CHCl ₃ (30 mL). A saturated aqueous solution of KOAc was added to the filtrate until the pH was neutral, and then a saturated aqueous solution of the Rochelle salt was added. The mixture was stirred vigorously, the layers were separated and the aqueous phase was extracted with CHCl _3. The combined organic extracts were washed with brine and dried over Na ₂ SO _4, filtered and concentrated. By column chromatography (1 to _{10% MeOH / CH 2 Cl 2} ) The product was purified to give a thick oily product (0.041 g, 47%).

Step C: Preparation of 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride: 1-(pyridin-3-ylmethyl)-1H-indazol-4-amine (0.040) in an ice/salt bath The solution of g, 0.18 mmol) in THF (1.1 mL) was cooled to -10. LHMDS (0.19 mL, 0.19 mmol, 1.0 M THF) was added and the mixture was stirred 15 min. To this dark solution was added 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester at 0 ° C (preparation) A; 0.030 g, 0.090 mmol) in THF (1.1 mL). The mixture was slowly warmed to 0 ° C and stirred at this temperature for 3 hours. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted with CH _{2 2} Cl. The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ dried, filtered, and concentrated. By prep TLC (1 mm, containing NH ₃ of _{15% MeOH / CH 2 Cl 2} ) Purification of the crude product was a pale brown powder 0.028 g of 7- (2- (4-methylpiperazin-1-yl) Ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide. This material was suspended in and add HCl (0.90 mL, 1.8 mmol, 2.0M Et 2 O solution) in MeOH (4.0 mL). The resulting suspension was stirred for 3 hours and then concentrated. The solid was slurried in Et ₂ O and separated by vacuum filtration. The solid was dried in vacuo to give EtOAc (EtOAc) MS (ES+APCI) m/z = 511 (M+H-3HCl).

Example 103

7-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indole Zin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride

Step A: Preparation of 2-(chloromethyl)-5-(trifluoromethyl)pyridine hydrochloride : (5-(trifluoromethyl)pyridin-2-yl)methanol (0.400 g, 2.26 mmol) CH ₂ Cl ₂ (4.4 mL) was cooled to 0 ℃ in the and adding _{SOCl 2 (0.494 mL, 6.77 mmol} ) of CH ₂ Cl ₂ solution (2.2 mL). The reaction was gradually warmed to ambient temperature over 1 hour and then stirred for an additional 1 hour. The reaction was concentrated and dried <RTI ID=0.0>

Step B: Preparation of 3-iodo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole : Add 3-iodo to a round bottom flask 4-nitro -1H- indazole (0.580 g, 2.01 mmol) and CH ₃ CN (10 mL). 2-Ter Butyl-1,1,3,3-tetramethylguanidine (0.890 mL, 4.41 mmol) was added and the mixture was stirred for 5 min. 2- (chloromethyl) -5- (trifluoromethyl) pyridine hydrochloride (0.512 g, 2.21 mmol) of CH ₃ CN solution (4 mL), and the mixture was stirred overnight at ambient temperature. The mixture was concentrated and diluted with saturated aqueous NH ₄ Cl (20 mL) and EtOAc (60 mL). The layers were mixed and separated and the organic phase was washed with brine, dried over Na ₂ SO ₄ will, filtered and concentrated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc)

Step C: Preparation of 1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole-4-amine: 3-iodo-4-nitro-1 at 0 °C Add zinc powder (0.339 g, 5.18) to a solution of ((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole (0.464 g, 1.04 mmol) in MeOH (10 mL) mmol), followed by the addition of saturated aqueous NH ₄ Cl (10 mL). The mixture was stirred at 0 ° C for 1 hour, then warmed to ambient temperature and stirred for an additional 1 hour. The mixture was diluted with MeOH and filtered. Saturated aqueous NH ₄ OAc was added to the filtrate, and the mixture was concentrated to remove the large amount of MeOH. Mixture was extracted with EtOAc, and the combined organic extracts were washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO _4, filtered and concentrated. The product was purified by column chromatography (25 to 100%EtOAcEtOAcEtOAc)

Step D: Preparation of 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl) -1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride: 7-(2-(4-methylpiperazine) chloride at 0 ° C Addition of POCl3 (0.0345 mL, 0.376 mmol) to a solution of -1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.0653 g, 0.188 mmol) in dry EtOAc (EtOAc) The mixture was stirred at 0 ° C for 30 minutes. Add DMA solution (1.0 mL) of 1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.055 g, 0.188 mmol), and gradually Warm to ambient temperature and stir overnight. The mixture was concentrated in vacuo and 2M LiOH (2.5 mL) was then evaporated. The mixture was stirred for 10 minutes. With CHCl ₃ (20 mL) and the mixture was diluted with saturated aqueous NaHCO _3, and the layers were mixed and separated. The aqueous phase was then extracted with CHCl ₃ and the combined organic layers were washed with brine and dried over Na ₂ SO _4, filtered and concentrated. By preparative TLC (adding 1% 7N NH ₃ / MeOH of 15% MeOH / CH2Cl ₂₎ The product was purified, to give a pale brown solid 7- (2- (4-methylpiperazin-1-yl) ethoxy -N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-methyl Indoleamine (0.028 g). The solid was dissolved in MeOH (2OmL) and EtOAc ( ₁ . The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et ₂ O and finally washed with hexane, and dried in vacuo to give the title compound (0.032 g, 24%). MS (ES+APCI) m/z = 579 (M+H-3HCl).

Example 104

N-(1-((1-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-( 4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Step A: Preparation of 3-(bromomethyl)-1-methylpyridine-2(1H)-one : Add 1,3-dimethylpyridine-2(1H)-one (0.54 g, 4.4 mmol) to In CCl ₄ (100 mL). N-bromosuccinimide (0.78 g, 4.4 mmol) and benzamidine peroxide (0.11 g, 0.44 mmol) were added and the reaction mixture was refluxed for 3 h. The reaction was cooled, filtered and concentrated. The residue was suspended in Et ₂ O (10 mL) and filtered to give a solid of 3- (bromomethyl) -1-methyl-pyridin -2 (1H) - one (0.29 g, 32% yield).

Step B: Preparation of 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridine-2(1H)-one : 3-iodo-4- Nitro-1H-carbazole (0.38 g, 1.3 mmol) was reacted with K ₂ CO ₃ (0.36 g, 2.6 mmol) in DMF (4 mL) for 15 min. 3-(Bromomethyl)-1-methylpyridine-2(1H)-one (0.28 g, 1.4 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with _{CH 2 Cl 2 (30 mL)} , filtered, and concentrated. The residue was partitioned between CHCl ₃ and saturated aqueous NaHCO _3. The organic layer was dried over MgSO ₄ and concentrated. The residue was suspended in EtOAc (EtOAc) (EtOAc)EtOAc. Methylpyridine-2(1H)-one (0.27 g, 50% yield).

Step C: Preparation of 3-((4-amino-1H-indazol-1-yl)methyl)-1-methylpyridine-2(1H)-one : 3-((3-iodo-4-) Nitro-1H-indazol-l-yl)methyl)-1-methylpyridine-2(1H)-one (0.26 g, 0.63 mmol) was added to MeOH (6 mL) and cooled to 0. Zinc (0.21 g, 3.2 mmol) was added to the reaction mixture. Dropwise addition of saturated aqueous NH ₄ Cl (6 mL) and the reaction mixture was stirred at ambient temperature for 90 minutes. The reaction was diluted with MeOH (50 mL) and stirred for 5 min and filtered. ₄ OAc and NH filtrate was diluted with saturated MeOH was removed in vacuo. The aqueous mixture was extracted with CHCl _3. The organic layer was washed with brine, dried over MgO _4, and concentrated to a solid to give 3 - ((4-amino -1H- indazol-1-yl) methyl) -1-methyl-pyridin -2 (1H) - Ketone (0.12 g, 71% yield).

Step D: Preparation of N-(1-((1-methyl-2-yloxy-1,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7- (2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride : 7-(2-(4-A) The piperazine-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.072 g, 0.21 mmol) was added to EtOAc (1 mL) and cooled to EtOAc. Phosphorus oxychloride (0.038 mL, 0.41 mmol) was added and the reaction mixture was stirred for 30 min. Add 3-((4-Amino-1H-indazol-1-yl)methyl)-1-methylpyridine-2(1H)-one (0.035 g, 0.14 mmol) and stir the reaction mixture at ambient temperature Overnight. The reaction was concentrated and then suspended in 2M LiOH (2 mL). The resulting mixture was stirred for 30 minutes and then diluted with CHCl3 and saturated _aqueous NaHCO. The layers were separated and the aqueous phase was extracted with CHCl _3. The combined organic layers were dried over MgSO ₄ and concentrated. The residue was purified by preparative thin layer chromatography (1: 62.3 M NH MeOH ₃ of: CH ₂ Cl ₂ solution) was purified, was added to MeOH (2 mL) and stirred with HCl ₍₂ M Et 2 O solution, 2 mL) reaction. The mixture was stirred for 60 minutes and then concentrated. The obtained solid was suspended in Et ₂ O and filtered to give N-(1-((1-methyl-2- oxo-1,2-dihydropyridin-3-yl)methyl)-1H as a solid. -oxazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (0.035 g, 41% yield). MS (ES+APCI) m/z = 541 (M+H-2HCl).

Example 105

N-(1-((6-ethoxypyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-A) Piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the procedure of Example 104 using 1-(bromomethyl)-3-methoxybenzene instead of 3-(bromomethyl)-1-methylpyridine-2(1H)-one. MS (ES+APCI) m/z = 555 (M+H).

Example 106

N-(1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl) Ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

Prepared according to the procedure of Example 104 using 4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride instead of 3-(bromomethyl)-1-methylpyridine-2(1H)-one. MS (ES+APCI) m/z = 514 (M+H).

Example 107

7-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-(2-(pyridin-2-yl)ethyl)-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-iodo-4-nitro-1-(2-(pyridin-2-yl)ethyl)-1H-indazole : 2-tert-butyl-1,1,3,3- Tetramethyl-hydrazine (0.48 mL, 2.4 mmol) was added to 3-iodo-4-nitro-1H-indazole (0.30 g, 1.0 mmol) and 2-(2-bromoethyl)pyridine hydrobromide ( 0.30 g, 1.1 mmol) in the in CH ₃ CN (4 mL) mixture. The mixture was stirred at ambient temperature overnight, diluted with H ₂ O (35 mL), stirred for 30 min, and then extracted with CHCl _3. The combined organic extracts were dried over MgSO ₄ and concentrated. The residue was purified by EtOAc (EtOAc) elute 34%).

Step B: 7-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-(2-(pyridin-2-yl)ethyl)-1H-indazole-4 -yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride : 3-iodo-4-nitro-1-(2-(pyridine-2-) according to Example 104 Step CE Substituting ethyl)-1H-carbazole for 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridine-2(1H)-one preparation. MS (ES+APCI) m/z = 525 (M+H).

Example 108

N-(1-((1H-benzo[d]imidazol-5-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl) Ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride

According to the method of Example 104, 3-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester and 6-(bromomethyl)-1H-benzo[d]imidazole-1 were used. Preparation of a mixture of -butyl formate instead of 3-(bromomethyl)-1-methylpyridine-2(1H)-one. MS (ES+APCI) m/z = 550 (M+H).

Example 109

N-(1-(2,4-difluorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine- 3-methylamine

Step A: 1-(2,4-Difluorobenzyl)-4-nitro-1H-indazole: 4-nitro-1H-carbazole (0.200 g, 1.226 mmol) cooled to 0 °C KOH (0.103 g, 1.839 mmol) was added to the solution in acetone (3 mL). After 15 minutes at 0 °C, 1-(bromomethyl)-2,4-difluorobenzene (0.173 mL, 1.349 mmol) was added. The mixture was stirred at ambient temperature EtOAc (EtOAc m.) Nitro-1H-carbazole (0.142 g, 40% yield).

Step B: 1-(2,4-Difluorobenzyl)-1H-indazole-4-amine: 1-(2,4-difluorobenzyl)-4-nitro-1H-carbazole (0.142 g, 0.491 mmol), a solution of ammonium chloride (0.013 g, 0.245 mmol) in 4:1 v/v EtOH / water (5 mL). The mixture was concentrated and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Mg, 75% yield).

Step C: N-(1-(2,4-Difluorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a Pyridine-3-carboxamide: 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.070 g, 0.296 mmol) and 2M oxalic acid chloride The methyl chloride solution (0.163 mL, 0.326 mmol) was suspended in dichloromethane (2 mL) and mp. The mixture was stirred for a few minutes and then treated with a solution of 1-(2,4-difluorobenzyl)-1H-indazole-4-amine (0.084 g, 0.326 mmol) in ca. Diisopropylethylamine (0.062 mL, 0.356 mmol) was added. After stirring the mixture overnight, the residue was shaken in water/dichloromethane and the suspension solid was collected by filtration to give N-(1-(2,4-difluorobenzyl)-1H-indazol-4-yl) -7-(2-Methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.070 g, 50% yield). MS (APCI) m/z = 478 (M + H).

Example 110

N-(1-(cyclopropylmethyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamidine amine

Substituting 1-(2,4-difluorobenzyl)-1H-indazole-4 with 1-(cyclopropylmethyl)-1H-indazole-4-amine in step C according to the method of Example 109 - Amine is prepared. MS (APCI) m/z = 406 (M + H).

Example 111

7-(2-methoxyethoxy)-N-(1-(pyridin-4-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3- Formamide

Substituting 1-(pico-4-ylmethyl)-1H-indazole-4-amine for 1-(2,4-difluorobenzyl)-1H-carbazole according to the method of Example 109 4-Amine was prepared. MS (APCI) m/z = 443 (M + H).

Example 112

7-(2-methoxyethoxy)-N-(1-(pyridin-2-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3- Formamide

Substituting 1-(pico-2-ylmethyl)-1H-indazol-4-amine for 1-(2,4-difluorobenzyl)-1H-carbazole according to the method of Example 109 4-Amine was prepared. MS (APCI) m/z = 443 (M + H).

Example 113

7-(2-methoxyethoxy)-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide

Substituting 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-amine for 1-(2,4-difluorobenzene) according to the method of Example 109 Methyl)-1H-indazole-4-amine was prepared. MS (APCI) m/z = 450 (M+H).

Example 114

N-(1-(4-Methoxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3 -Procarbamide

Substituting 1-(4-methoxybenzyl)-1H-indazol-4-amine for 1-(2,4-difluorobenzyl)-1H-indole according to the method of Example 109 The azole-4-amine was prepared. MS (APCI) m/z = 472 (M + H).

Example 115

N-(1-(cyclohexylmethyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy) Oxazo[1,2-a]pyridine-3-carboxamide

Substituting 1-(cyclohexylmethyl)-1H-indazole-4-amine for 1-(2,4-difluorobenzyl)-1H-indazole-4- in step C according to the method of Example 109 The amine is prepared. MS (APCI) m/z = 448 (M+H).

Example 116

3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl) Piperidine-1-carboxylic acid tert-butyl ester

Substituting 3-((4-amino-1H-indazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester for 1-(2,4-) according to the method of Example 109 Preparation of difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 549 (M+H).

Example 117

(R)-3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl )methyl) piperidine-1-carboxylic acid tert-butyl ester

Substitution of (R)-3-((4-amino-1H-indazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester in place of 1-(1) according to the method of Example 109 Preparation of 2,4-difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 549 (M+H).

Example 118

7-(2-methoxyethoxy)-N-(1-((2-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide

Substituting 1-((2-methylpyridin-3-yl)methyl)-1H-indazole-4-amine for 1-(2,4-difluorobenzyl) according to the method of Example 109 Preparation of -1H-carbazole-4-amine. MS (APCI) m/z = 457 (M+H).

Example 119

N-(1-(3-(Benzyloxy)benzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a Pyridine-3-carboxamide

Substituting 1-(3-(benzyloxy)benzyl)-1H-indazole-4-amine for 1-(2,4-difluorobenzyl) in step C according to the method of Example 109 Preparation of -1H-carbazole-4-amine. MS (APCI) m/z = 548 (M + H).

Example 120

7-(2-methoxyethoxy)-N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyridine-3-carboxamide

Substituting 1-(4-(trifluoromethyl)benzyl)-1H-indazol-4-amine for 1-(2,4-difluorobenzyl)-1H-carbazole according to the method of Example 109 4-Amine was prepared. MS (APCI) m/z = 510 (M+H).

Example 121

7-(2-methoxyethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3- Formamide

Substituting 1-(pico-3-ylmethyl)-1H-indazol-4-amine for 1-(2,4-difluorobenzyl)-1H-carbazole according to the method of Example 109 4-Amine was prepared. MS (APCI) m/z = 443 (M + H).

Example 122

4-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl) Piperidine-1-carboxylic acid tert-butyl ester

Substituting 1-(2,4-amino-4-H-indazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester for 1-(2,4-) according to the method of Example 109 Preparation of difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 549 (M+H).

Example 123

2-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl) Morpholine-4-carboxylic acid tert-butyl ester

Substituting 1-(2,4-amino-1H-indazol-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester for 1-(2,4-) according to the method of Example 109 Preparation of difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 551 (M + H).

Example 124

7-(2-methoxyethoxy)-N-(1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide

Substituting 1-((6-methylpyridin-3-yl)methyl)-1H-indazole-4-amine for 1-(2,4-difluorobenzyl) according to the method of Example 109 Preparation of -1H-carbazole-4-amine. MS (APCI) m/z = 457 (M+H).

Example 125

N-(1-Benzyl-1H-indazol-4-yl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide

According to the method of Example 109, 7-(2-methoxy) was replaced with 7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazole-4-amine, respectively. The preparation of ethoxy) imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 398 (M+H).

Example 126

N-(1-Benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Substituting imidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazole-4-amine for 7-(2-methoxyethoxy) according to the method of Example 109 Imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine were prepared. MS (APCI) m/z = 368 (M+H).

Example 127

N-(1-Benzyl-1H-indazol-4-yl)-7-ethoxyimidazo[1,2-a]pyridine-3-carboxamide

Substituting 7-(2-methoxy) with 7-ethoxyimidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-1H-indazole-4-amine according to the method of Example 109 The preparation of ethoxy) imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 412 (M + H).

Example 128

N-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

According to the method of Example 109, imidazo[1,2-a]pyridine-3-carboxylic acid and 1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazole-4-, respectively. Amine instead of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazole-4- The amine is prepared. MS (APCI) m/z = 376 (M+H).

Example 129

N-(1-(pyridin-2-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Substituting imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(pyridin-2-ylmethyl)-1H-indazole-4-amine for 7-(2-A) according to the method of Example 109 The preparation is carried out by oxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-(2,4-difluorobenzyl)-1H-indazol-4-amine. MS (APCI) m/z = 369 (M+H).

Example 130

N-(1-(3-hydroxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-methyl Guanamine

N-(1-(3-(Benzyloxy)benzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2- A] A solution of pyridine-3-carbamide (0.022 g, 0.040 mmol) in MeOH (2 mL) eluting with argon eluting with 10% palladium/carbon (0.002 g) And then attached to the hydrogen balloon. The mixture was stirred at ambient temperature overnight, filtered over EtOAc EtOAc EtOAc (EtOAc) -hydroxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.003 g, 18 %Yield). MS (APCI) m/z = 458 (M + H).

Example 131

7-(2-methoxyethoxy)-N-(1-(piperidin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3 -carbamidine hydrochloride

Treatment of 3-((4-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-methyl with 4N hydrochloric acid in dioxane (1 mL) at ambient temperature A solution of the decylamino)-1H-indazol-l-yl)methyl)piperidine-l-carboxylic acid tert-butyl ester (0.056 g, 0.10 mmol) in DCM (1 mL). The mixture was stirred at ambient temperature overnight and concentrated to give 7-(2-methoxyethoxy)-N-(1-(piperidin-3-ylmethyl)-1H-carbazole-4 as a brown oil. -yl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (0.0046 g, 93% yield). MS (APCI) m/z = 449 (M + H).

Example 132

N-(1-((1-Ethylpiperidin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1, 2-a]pyridine-3-carboxamide

Step A: 3-((4-Nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylic acid tert- butyl ester: 4-nitro-1H-carbazole at ambient temperature ( 0.200 g, 1.23 mmol) was added 60% sodium hydride (0.074 g, 1.84 mmol) in EtOAc (3 mL). After 30 minutes, tert-butyl 3-(toluenesulfonyloxymethyl)piperidine-1-carboxylate (0.544 g, 1.47 mmol) was added. The mixture was heated overnight at 100 ° C, diluted with water, extracted with EtOAc EtOAc EtOAc (EtOAc m. Glycol 3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.176 g, 40% yield).

Step B: 4-Nitro-1-(piperidin-3-ylmethyl)-1H-indazole: Treatment of 3-((4-nitro-1H-) with trifluoroacetic acid (0.4 mL) at ambient temperature A solution of decazol-1-yl)methyl)piperidine-l-carboxylic acid tert-butyl ester (0.118 g, 0.327 mmol) in DCM ( 1.6 mL) The solvent was concentrated and dried to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

Step C: 1-(3-((4-Nitro-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone: acetic anhydride (0.0158 mL, 0.168 mmol ) at ambient temperature Treatment of 4-nitro-1-(piperidin-3-ylmethyl)-1H-indazole (0.050 g, 0.139 mmol), triethylamine (0.097 mL, 0.699 mmol) in DCM (1 mL) The solution was stirred for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with DCM, dried (diluent-purified filter paper) and concentrated to give 1-(3-((4-nitro-1H-carbazole-1) as a yellow oil. -yl)methyl)piperidin-1-yl)ethanone (0.022 g, 52% yield).

Step D: 1-(3-((4-Amino-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone : 1-(3-((4-nitro-) A solution of 1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone (0.022 g, 0.073 mmol) in MeOH (1 mL) elut 0.002 g) treatment, flushing with argon, and subsequent attachment to a hydrogen balloon. The mixture was stirred at ambient temperature overnight, filtered over EtOAc EtOAc EtOAc EtOAc. Piperidin-1-yl)ethanone (0.020 g, 100% yield).

Step E: N-(1-((1-Ethylpiperidin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazolium [1,2-a]pyridine-3-carboxamide : 1-(3-((4-amino-1H-indazol-1-yl)methyl)piperidine-1) according to the procedure of Example 109 The preparation was carried out by replacing the 1-(2,4-difluorobenzyl)-1H-indazol-4-amine with ethyl ketone. MS (APCI) m/z = 491 (M + H).

Example 133

7-(2-methoxyethoxy)-N-(1-phenyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: 4-Nitro-1-phenyl-1H-carbazole : 2,6-dinitrobenzaldehyde (0.200 g, 1.020 mmol) and phenylhydrazine (0.120 mL, 1.224 mmol) were stirred at ambient temperature A mixture of EtOH (1.5 mL) and acetic acid (0.15 mL). The resulting red solution was concentrated and EtOAc (EtOAc)EtOAc. Stirring was continued for 2 hours at ambient temperature. The solution was concentrated to EtOAc (EtOAc) (EtOAc)EtOAc The oxime-treated filter paper was concentrated to give a brown solid which was purified eluted eluted eluted 0.140 g, 57% yield).

Step B: 1-Phenyl-1H-indazole-4-amine : 4-nitro-1-phenyl-1H-indazole (0.140 g, 0.585 mmol), ammonium chloride (0.016 g, 0.293 mmol) The solution in 4:1 v/v EtOH / water (5 mL). The mixture was concentrated and EtOAc EtOAc EtOAc m.

Step C: 7-(2-Methoxyethoxy)-N-(1-phenyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : Prepared according to the procedure of Example 109 using 1-phenyl-1H-indazole-4-amine instead of 1-(2,4-difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 428 (M+H).

Example 134

N-(1-Benzyl-5-bromo-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazole And [1,2-a]pyridine-3-carboxamide

Step A: 1-Benzyl-1H-indazole-4-amine : 1-Benzyl-4-nitro-1H-indazole (0.404 g, 1.595 mmol), ammonium chloride (0.043 g, 0.798) A solution of 4:1 v/v EtOH / water (10 mL) was taken from &lt;RTI ID=0.0&gt; The mixture was concentrated and the residue was crystallisjjjjjjjjjjj

Step B: 1-Benzyl-5-bromo-1H-indazole-4-amine : Treatment of 1-benzyl-1H- with N-bromosuccinimide (0.069 g, 0.39 mmol) at ambient temperature A solution of oxazol-4-amine (0.087 g, 0.39 mmol) in DMF (2 mL) The mixture was diluted with water, extracted with EtOAc (EtOAc EtOAc (EtOAc m. -1H-indazole-4-amine (0.005 g, 4% yield).

Step C: N-(1-Benzyl-5-bromo-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3 -Metformamide : Substituting 1-benzyl-2-bromo-1H-indazole-4-amine for 1-(2,4-difluorobenzyl)-1H-carbazole according to the procedure of Example 109 4-amine was prepared. MS (APCI) m/z = 522 (M+2H).

Example 135

N-(1-Benzyl-7-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazole And [1,2-a]pyridine-3-carboxamide

Step A: 1-Benzyl-5-chloro-1H-indazole-4-amine : Treatment of 1-benzyl-1H- with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambient temperature A solution of oxazol-4-amine (0.080 g, 0.36 mmol) in DMF (2 mL) The mixture was diluted with water, extracted with EtOAc (EtOAc EtOAc (EtOAc m. -1H-indazole-4-amine (0.035 g, 38% yield).

Step B: N-(1-Benzyl-7-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3 -Metformamide: 1-(2,4-difluorobenzyl)-1H-indazole was replaced by 1-benzyl-7-chloro-1H-indazole-4-amine according to the procedure of Example 109. 4-amine was prepared. MS (APCI) m / z = 476 (M + H).

Example 136

N-(1-Benzyl-5,7-dichloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3 -Procarbamide

Step A: 1-Benzyl-5,7-dichloro-1H-indazol-4-amine: Treatment of 1-benzyl group with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambient temperature A solution of -1H-indazole-4-amine (0.080 g, 0.36 mmol) in DMF (2 mL) The mixture was diluted with water, extracted with EtOAc (EtOAc EtOAc (EtOAc m. -Dichloro-1H-indazole-4-amine (0.008 g, 9% yield).

Step B: N-(1-Benzyl-5,7-dichloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a] Pyridine-3-carbamide: substituting 1-benzyl 2,7-dichloro-1H-indazole-4-amine for 1-(2,4-difluorobenzyl) according to the procedure of Example 109 Preparation of -1H-carbazole-4-amine. MS (APCI) m/z = 510 (M+).

Example 137

N-(1-Benzyl-5-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamidine amine

Step A: 1-Benzyl-5-chloro-1H-indazole-4-amine: Treatment of 1-benzyl-1H- with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambient temperature A solution of oxazol-4-amine (0.080 g, 0.36 mmol) in DMF (2 mL) The mixture was diluted with water, extracted with EtOAc (EtOAc EtOAc (EtOAc m. -1H-indazole-4-amine (0.035 g, 38% yield).

Step B: N-(1-Benzyl-5-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3 -Metformamide: 1-(2,4-difluorobenzyl)-1H-indazole was replaced by 1-benzyl-5-chloro-1H-indazole-4-amine according to the procedure of Example 109. 4-amine was prepared. MS (APCI) m/z = 476 (M+).

Example 138

N-(1-((6-isopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)B Oxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-chloropicolinate: To a solution of 6-chloropicolinic acid (5.01 g, 31.8 mmol) in EtOH (100 mL). The reaction was heated to reflux overnight, cooled to rt. The residue was dissolved in DCM (100 mL) and aqueous NaOH (2M) was then applied. The aqueous layer was then extracted with DCM. The combined organic extracts were combined, dried (Na ₂ SO ₄₎ and concentrated under reduced pressure to give the desired product (85%).

Step B: Preparation of ethyl 6-(prop-1-en-2-yl)pyridinecarboxylate: The first flask was charged with 1,4-dioxane/H ₂ O (50 mL / 10 mL). The flask was cooled to 0 ° C and a vacuum was applied for 20 min. The second flask was charged with ethyl 6-chloropicolinate (4.200 g, 22.63 mmol), isopropenyl trifluoroborate (4.353 g, 29.42 mmol), K ₂ CO ₃ (4.378 g, 31.68 mmol), Palladium ethoxide (0.1524 g, 0.6789 mmol) and sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.6959 g, 1.358 mmol). The flask was also evacuated by vacuum and backfilled N ₂ 3 times. A degassed cold dioxane/H ₂ O solution was added to the second flask, evacuated with vacuum and backfilled with argon 5 times. The reaction mixture was then heated to 80 ° C for 3 hours. The reaction was cooled to ambient temperature, filtered and concentrated. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCO _3, dried (Na ₂ SO ₄₎ and concentrated to give the desired product, which was used without further purification.

Step C: Preparation of ethyl 6-isopropylpicolinate: added to ethyl 6-(prop-1-en-2-yl)pyridinecarboxylate (4.63 g, 24.2 mmol) in EtOH (50 mL) Pd/C (0.61 g, 0.573 mmol). The reaction mixture was purged three times with nitrogen and hydrogen each. A hydrogen balloon was applied to the reaction for 3 hours. The reaction was then flushed with nitrogen through a diatomaceous earth Filter and wash with EtOH (100 mL). The solvent was removed under reduced pressure to give the desired product (93%).

Step D: Preparation of (6-isopropylpyridin-2-yl)methanol: Addition of LAH to ethyl 6-isopropylpicolinate (4.63 g, 24.0 mmol) in THF (50 mL) (0.909 g, 24.0 mmol). The cooling bath was removed and the reaction mixture was stirred for 2 h and was quenched with sodium sulfate dehydrate. The reaction mixture is then passed through the diatomaceous earth Filtered and washed with Et ₂ O (200 mL). The filtrate was concentrated under reduced pressure to give the desired material (j.

Step E: Preparation of 2-(chloromethyl)-6-isopropylpyridine hydrochloride: (6-isopropylpyridin-2-yl)methanol dissolved in DCM (20 mL) Dichloromethane (12.3 g, 104 mmol) was added to 3.13 g, 20.7 mmol). The cooling bath was removed and the reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure to give the desired material (98%).

Step F: Preparation of 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-carbazole: 3- dissolved in DMF (50 mL) Add bromo-4-nitro-1H-indazole (4.91 g, 20.3 mmol) with 2-(chloromethyl)-6-isopropylpyridine hydrochloride (4.18 g, 20.3 mmol) and K ₂ CO ₃ ( 8.41 g, 60.8 mmol). The reaction mixture was stirred for 18 hours. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (100 mL). The resulting suspension was washed with water and brine. The combined organic extracts were dried (Na ₂ SO _4), and filtered by silica gel flash chromatography (1: 2 EtOAc / hexanes) to give the desired product (67%).

Step G: Preparation of 1-((6-isopropylpyridin-2-yl)methyl)-1H-indazole-4-amine: 3-bromo-1-((()) Pd(OH) _{2 /} C (1.21 g, 1.72 mmol) was added to 6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (2.10 g, 5.60 mmol). The reaction mixture was purged 3 times with each of N ₂ and H ₂ . H ₂ is then fed to the reaction to 45 psi. The reaction mixture was stirred for 4 hours and passed through diatomaceous earth filter. Washing diatomaceous earth with EtOH (200 mL) The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc

Step H: Preparation of 1 N-(1-((6-isopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: to 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[ Lithium 1,2-a]pyridine-3-carboxylate (188 mg, 0.595 mmol) was added with NMP (5 mL, and the mixture was evaporated to dryness in MgSO ₄ oven oven. The starting material was dissolved using a heat gun. The flask was cooled to 0 ° C and 2,4,6-trichlorobenzhydrin chloride (94.2 μL, 0.590 mmol) was added dropwise. After the addition was completed, the cooling bath was removed and the reaction mixture was further stirred for 1 hour. The reaction mixture changed from a clear solution to a slight turbidity. 1-((6-Isopropylpyridin-2-yl)methyl)-1H-indazol-4-amine (120 mg, 0.451 mmol) was added in one portion to the reaction mixture and the mixture was heated to <RTI ID=0.0> It lasted 5 hours. NMP (at the same bath temperature) was removed by vacuum distillation until the reaction mixture became a thick oil. NaOH (1.8 mmol) dissolved in H ₂ O (10 mL) was added to this thick oil and the mixture was stirred at 80 ° C for 30 min. The solution was cooled to ambient temperature and washed with saturated NH ₄ Cl and the pH value was adjusted dark solution of pH 12 to 13 The solution was cooled to 0 ° C and H ₂ O (20 mL) was added. Stirring was continued for 30 minutes during which time solids precipitated out of solution. Saturated NaHCO ₃ and the mixture was filtered and the filtrate was washed with H ₂ O. The resulting solid was dissolved in DCM, dried (Na ₂ SO _4), filtered and concentrated. The residue was triturated with MTBE to give the final product (15%). MS (ES+APCI) m/z = 553.1 (M+H).

Example 139

N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-A) Piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 1-isopropyl-5-methyl-1H-pyrazole-3-carboxylate: 2,4-dioxy valeric acid dissolved in acetic acid (100 mL) at 0 °C Isopropyl hydrazine (9.42 g, 127 mmol) was added dropwise to ethyl acetate (20.1 g, 127 mmol). The cooling bath was removed and the reaction mixture was stirred for 2 h. The reaction mixture was then diluted with _{EtOAc / H 2 O (300 mL} / 100 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (100 mL), washed with H ₂ O (50 mL) and brine (50 mL). The organic layer was dried (Na ₂ SO ₄₎ and concentrated. The residue was purified by EtOAc EtOAc (EtOAc)

Step B: Preparation of (1-isopropyl-5-methyl-1H-pyrazol-3-yl)methanol : 1-isopropyl-5-A in THF (50 mL) at 0 ° LAH (1.49 g, 39.1 mmol) was added to ethyl-1H-pyrazole-3-carboxylate (7.68 g, 39.1 mmol). The cooling bath was removed and the reaction mixture was stirred for 2 h and carefully quenched with sodium sulfate decahydrate. Reaction mixture via diatomaceous earth Filtered and washed with Et ₂ O (200 mL). The filtrate was concentrated under reduced pressure to give the desired product (yield: 88%).

Step C: Preparation of 3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazole hydrochloride : (1-isopropyl in DCM (20 mL) Dichloroaluminium (20 g, 172 mmol) was added to the group 5-methyl-1H-pyrazol-3-yl)methanol (5.3 g, 34 mmol). The cooling bath was removed and the reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure to give the desired product (99%).

Step D: Preparation of N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-(2- (4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide : according to the method of Example 66 (Steps F to H), used in Step F 3-(Chloromethyl)-1-isopropyl-5-methyl-1H-pyrazole hydrochloride in place of 2-(chloromethyl)-6-isopropylpyridine hydrochloride from 3-(chloro Preparation of methyl)-1-isopropyl-5-methyl-1H-pyrazole hydrochloride. MS (ES+APCI) m/z = 556.1 (M+H).

Example 140

N-(1-(3-methoxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3 -Procarbamide

According to the method of Example 139, from 7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid, 3-iodo-4-nitro-1H-carbazole and 1-(bromo Preparation of methyl)-3-methoxybenzene. MS (ES+APCI) m/z = 472.3 (M+H).

Example 141

N-(1-(3-Chlorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-methyl Guanamine

According to the method of Example 139, from 7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid, 3-iodo-4-nitro-1H-carbazole and 1-(bromo Preparation of methyl)-3-chlorobenzene. MS (ES+APCI) m/z = 476.2 (M+H).

Example 142

7-(2-methoxyethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide

According to the method of Example 139, 7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid, 3-iodo-4-nitro-1H-carbazole and 2-(bromo) Preparation of methyl)-6-methylpyridine. MS (ES+APCI) m/z = 457.2 (M+H).

Example 143

7-(2-methoxyethoxy)-N-(1-(3-methylbenzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3- Formamide

According to the method of Example 139, from 7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid, 3-iodo-4-nitro-1H-carbazole and 1-(bromo Preparation of methyl)-3-methylbenzene. MS (ES+APCI) m/z = 456.3 (M+H).

Example 144

N-(1-Benzyl-1H-indazol-4-yl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-fluoroimidazo[1,2-a]pyridine-3-carboxylate : 5-fluoropyridin-2-amine (1 g, 8.92 mmol) and 2,3-dichloro-3- Ethyl oxypropionate (39.6 g, 10.7 mmol, 5% benzene solution) was added to the flask along with 75 mL of ethanol and stirred at ambient temperature overnight. The material was purified using EtOAc EtOAc (EtOAc:EtOAc) MS (ES+APCI) m/z = 209.2 (M+H).

Step B: Preparation of 6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid : ethyl 6-fluoroimidazo[1,2-a]pyridine-3-carboxylate (0.10 g, 0.48 mmol) Lithium hydroxide monohydrate (0.020 g, 0.48 mmol) was added to a mixture of water, THF and ethanol (1:2:1) and heated in a sealed vial at 65 °C for 6 hours. The solvent was removed by rotary evaporation to give 87 mg of desired material. MS (ES+APCI) m/z = 181.1 (M+H).

Step C: Preparation of 1-benzyl-4-nitro-1H-carbazole : 4-nitro-1H-carbazole (1.0 g, 6.13 mmol) and potassium carbonate (1.69 g, 12.3 mmol) were added to DMF Medium and stirred overnight at room temperature. Water (50 mL) was added and the~~~~~~ The crude brown solid was purified on silica gel using hexane/ethyl acetate. The first isolated product (730 mg) was determined by NMR to be the desired 1-benzyl residue.

Step D: Preparation of 1-benzyl-1H-indazole-4-amine : Ammonium chloride (0.043 g, 0.79 mmol) followed by Fe(0) (0.89 g, 15.95 mmol) dissolved in 4:1 1-Benzyl-4-nitro-1H-indazole (0.40 g, 1.59 mmol) in ethanol / water (10 mL). A single product was observed on HPLC. The solvent was removed and the residue was crystallised from EtOAc EtOAc EtOAc EtOAc MS (ES+APCI) m/z = 224.3 (M+H).

Step E: Preparation of N-(1-benzyl-1H-indazol-4-yl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide : 6 -fluoroimidazo [ A suspension of 1,2-a]pyridine-3-carboxylic acid (0.083 g, 0.46 mmol) was added to dichloromethane, and then dichloromethane (0.28 mL, 0.55 mmol) was slowly added. The mixture was stirred for 10 minutes, then 1-benzyl-1H-indazole-4-amine (0.10 g, 0.46 mmol, Step D) and N-ethyl-isopropylpropan-2-amine (0.11 mL, A solution of 0.60 mmol) was stirred for 2 hours. The solvent was concentrated and the obtained crude material was purified eluted eluted eluted eluted MS (ES+APCI) m/z = 386.4 (M+H).

Example 145

N-(1-Benzyl-1H-indazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A dry round bottom flask equipped with a reflux condenser and a nitrogen line was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole-1-carboxylic acid tert-butyl ester (16.7 mg, 0.057 mmol), N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a Pyridine-3-carbamide (23 mg, 0.052 mmol), Pd(PPh ₃ ) ₄ (3.0 mg, 0.003 mmol) and potassium carbonate (36 mg, 0.26 mmol). A water/DMF/CH ₃ CN mixture (1:1:4.5; 0.1:0.1:0.6 mL) was added to the flask, and the reaction mixture was degassed under nitrogen and heated at 80 ° C for 6 hours. The cooled reaction mixture was diluted with water and aq. The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute MS detected (ES+APCI) m/z = 534 (M+H).

Example 146

7-Ethyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

To a dry flask purged with nitrogen was charged N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide ( 150 mg, 0.34 mmol), tri-o-tolylphosphine (20 mg, 0.067 mmol), gin-dibenzylideneacetone dipalladium (0) (31 mg, 0.033 mmol), anhydrous DMF (4.5 mL) and tributyl (1-Ethoxyvinyl)stannane (0.13 mL, 0.39 mmol). The resulting mixture was immediately degassed under a nitrogen atmosphere, triethylamine (0.056 mL, 0.40 mmol) was then applied and the flask was warmed at 100 ° C for 6 hours. Concentrated aqueous hydrochloric acid (0.5 mL) was added to the cooled mixture and stirring was continued at ambient temperature for 2 h. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin-layer chromatography eluting with EtOAc (EtOAc) MS detected (ES+APCI) m/z=410 (M+H).

Example 147

N-(1-Benzyl-1H-indazol-4-yl)-7-(1-hydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

Treatment of 7-acetamido-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a] with an excess of sodium borohydride (3.7 mL, 0.10 mmol) at ambient temperature A solution of pyridine-3-carbamide (Example 146; 10 mg, 0.024 mmol) in 1:1 THF/MeOH mixture (0.2 mL). The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography on EtOAc (EtOAc) elute MS detected (ES+APCI) m/z = 412 (M+H).

Example 148

N-(1-Benzyl-1H-indazol-4-yl)-7-(1-(N-morpholinyl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide

7-Ethyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 146; 10.8 mg, 0.026 mmol Morpholine (3 equivalents) was added to a solution in DCM (0.6 mL). The resulting solution was stirred at ambient temperature for 2 h then added sodium triethyl succinyl borohydride (28 mg, 0.13 mmol, 5 eq.). The resulting suspension was stirred at ambient temperature for 100 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic extracts were dried with anhydrous sodium The crude product was subjected to preparative thin layer chromatography eluting with MeOH/D. MS detected (ES+APCI) m/z = 481 (M+H).

Example 149

7-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-((2-methylthiazol-5-yl)methyl)-1H-indazole-4- Imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 5-(bromomethyl)-2-methylthiazole : Addition to a solution of (2-methylthiazol-5-yl)methanol (335 mg, 2.59 mmol) in anhydrous DMF (3 mL) Triphenylphosphine (1.02 g, 3.89 mmol) and carbon tetrabromide (1.29 g, 3.89 mmol). The resulting mixture was stirred at ambient temperature overnight (ca. 18 h) then diluted with water (10 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (EtOAc m. The crude product was purified by flash chromatography eluting with EtOAc (EtOAc:EtOAc)

Step B: Preparation of 5-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole : 3-iodo-4- at ambient temperature under a nitrogen atmosphere Potassium carbonate (422 mg, 3.05 mmol) and 5-(bromomethyl)-2-methylthiazole were added to a solution of nitro-1H-carbazole (441 mg, 1.53 mmol) in anhydrous DMF (3 mL) 440 mg, 2.30 mmol). The resulting mixture was stirred overnight (about 18 hours) at ambient temperature. The reaction mixture was diluted with water (10 mL) and EtOAc (20 mL). The phases were separated and the aqueous extracted with EtOAc (2 <RTI ID=0.0> The combined organic extracts were concentrated and purified EtOAcqqqqqqq

Step C: Preparation of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazole-4-amine: to 5-((3-iodo-4-nitro-1H) Add iron powder (463 mg, 8.30 mmol) to a solution of oxazol-1-yl)methyl)-2-methylthiazole (332 mg, 0.830 mmol) in EtOH / water (4:1, 10 mL) And ammonium chloride (44.4 mg, 0.83 mmol). The resulting mixture was heated at 85 ° C for 3 hours under vigorous magnetic stirring. The mixture was cooled to ambient temperature, EtOAc (EtOAc) The resulting mixture was heated at 85 &lt;0&gt;C for 20 min then cooled to 45 &lt;0&gt;C, filtered over EtOAc (EtOAc)EtOAc. The combined organic filtrates were concentrated with EtOAc EtOAc m.

Step D: Preparation of N-(3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylperidine) Pyrazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide: bis(trimethyldecyl)amine lithium (1.0) at ambient temperature under nitrogen atmosphere Treatment of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine (40 mg, 0.11 mmol) in dry THF Solution in 3 mL). The resulting brown solution was added dropwise to ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (35.9 mg, 0.11 mmol ) in a cold (ice-water) solution in anhydrous THF (3 mL). The reaction mixture was allowed to warm to ambient temperature and diluted with water (10 mL). The resulting mixture was sufficiently extracted with ethyl acetate and dichloromethane. The combined organic extracts were dried with sodium sulfate. The crude oil was subjected to preparative thin layer chromatography on ruthenium dioxide using MeOH / DCM as solvent.

Step E: Preparation of 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((2-methylthiazol-5-yl)methyl)-1H-indole Zin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : treatment of N-(3-iodo-1-() with Pd/C (Degussa, moist, 10% by weight, 2 mg) (2-methylthiazol-5-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1 A solution of 2-a]pyridine-3-carboxamide (11.5 mg, 0.018 mmol) in dry Et.sub.2 (1 mL). The reaction was diluted with DCM, the catalyst was removed by filtration and the filtrate was concentrated to give crude. The crude product was subjected to preparative thin layer chromatography on ruthenium dioxide using MeOH / MeOH / DCM as solvent. MS detected (ES+APCI) m/z = 531 (M+H).

Example 150

7-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4- Imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4- amine : 3-iodo-1-((6-methylpyridin-2-yl) A solution of methyl)-4-nitro-1H-indazole (Example 89, Step AB; 1.00 g, 2.54 mmol) in MeOH (25 mL) Zinc powder (0.829 g, 12.7 mmol) was added and the mixture was stirred for 10 minutes. Saturated aqueous NH ₄ Cl (25 mL) and the mixture was stirred for 2 hours at 0 ℃ force, and then warmed to ambient temperature and stirred for 2 hours. Then saturated aqueous NH ₄ Cl (12.5 mL) and the mixture was further stirred for 2 hours at ambient temperature. The mixture was diluted with MeOH and filtered. Saturated aq NH ₄ OAc was added to the filtrate and the mixture was concentrated to remove the large amount of MeOH. The mixture and the combined organic extracts were then extracted, washed with saturated aqueous NaHCO ₃ and dried with brine and Na ₂ SO _4, filtered and concentrated with EtOAc. By column chromatography (2 to 20% IPA / CHCl ₃₎ The crude material was purified to give 0.428 g (70%) of the desired product as an orange solid.

Step B: Preparation of 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)-1H-indole Zin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide : LHMDS (1.595 mL, 1.595 mmol, 1.0 M THF) was added dropwise to 1-((6-) at 0 °C. A solution of methylpyridin-2-yl)methyl)-1H-indazole-4-amine (0.190 g, 0.7974 mmol) in THF (4 mL) The mixture was stirred at 0 ° C for 10 minutes, followed by one-time addition of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate. (Preparation A; 0.5566 g, 1.674 mmol) and the mixture was stirred overnight. The reaction mixture was diluted with saturated aqueous NaHCO ₃ and _extracted with CH ₂ Cl. The combined organic layer was dried over Na ₂ SO _4, filtered and concentrated. By column chromatography (using 5% NH ₄ OH / 5 to 20% MeOH MeOH sum / CH ₂ Cl ₂₎ Purification of the crude product to give the desired product 0.254 g (61%) as a beige powder. MS (ES+APCI) m/z = 525 (M+H).

Example 151

7 -(2-methoxyethoxy)-N-(1-phenethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the procedure of Example 109 using 1-phenylethyl-1H-indazole-4-amine instead of 1-(2,4-difluorobenzyl)-1H-indazole-4-amine. MS (APCI) m/z = 456 (M+H).

Example 152

N-(1-Benzyl-1H-indazol-4-yl)-7-cyanoimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 7-cyanoimidazo[1,2-a]pyridine-3-carboxylate : Add 2-chloro-3-side oxygen to 2-aminoisonicotinonitrile (4.6 g, 38.6 mmol) Ethyl propyl propionate (184 mL, 57.9 mmol) and EtOH (10 mL), and the mixture was warmed to 75 ° C for 6 hr. The precipitated solid was removed by vacuum filtration and partitioned between saturated aqueous NaHCO ₃ and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated to give 1.4 g of unreacted amine - isonicotinonitrile (30%). The filtrate was concentrated to give a beige solid, which was partitioned between EtOAc and saturated _aqueous NaHCO. Drying the aqueous layer was extracted with EtOAc and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated to give 6.4 g beige solid. The crude material was purified by EtOAc EtOAc EtOAc EtOAc

Step B: Preparation of 7-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid : ethyl 7-cyanoimidazo[1,2-a]pyridine-3-carboxylate (2.23 g, 10.4 mmol LiOH (0.248 g, 10.4 mmol) was added to a mixture of 100 mL THF: EtOH: water (1:2:1). The reaction mixture was stirred at ambient temperature overnight. The reaction was concentrated and diluted with H.sub.2. The precipitate was removed by EtOAc (EtOAc)EtOAc.

Step C: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-cyanoimidazo[1,2-a]pyridine-3-carboxamide: to 7-cyanoimidazole And [1,2-a]pyridine-3-carboxylic acid (0.0527 g, 0.282 mmol) in 0.200 mL of CH ₂ Cl ₂ was added 1 drop of DMF, followed by addition of chloroform (1.6 equivalents, 2 M CH ₂ Cl ₂ solution). The reaction was stirred for 5 minutes until foaming ceased. -1H- added 1-benzyl-indazol-4-amine (0.0629 g, 0.282 mmol) in a solution of ₂ CH ₂ Cl 0.600 mL, followed by addition of DIEA (1.2 eq.). The reaction was stirred at ambient temperature overnight. The reaction was concentrated and washed with Et ₂ O, water, 2M Na ₂ CO _3, then water, and finally the solid was washed with Et ₂ O, to give the desired product as a beige solid 0.072 g (65%). MS (ES+APCI) m/z = 393 (M+H).

Example 153

N-(1-Benzyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine 3-carbamamine

Step A: Preparation of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate: to 7-(2-(4- Addition of ethyl methyl piperazine-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (preparation A; 0.239 g, 0.719 mmol) in THF (3 mL) H ₂ O, followed by the addition of LiOH (0.0344 g, 1.44 mmol), and stirred at ambient temperature overnight. The reaction was transferred to a sealed tube and heated to 100 ° C for 8 hours. The reaction mixture was concentrated to give 0.230 g, m.

Step B: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2 -a]pyridine-3-carbamide: to 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid lithium (0.0585 g, 0.189 mmol) in CH ₂ Cl ₂ in the solution is added 1 drop of DMF. Grass chloroform (1.1 eq., 2 M CH ₂ Cl ₂ solution) was added and the reaction was stirred at ambient temperature until foaming ceased (about 5 min). 1-Benzyl-1H-indazole-4-amine (0.042 g, 0.189 mmol) was added followed by DIEA (1.2 eq.). The reaction was stirred at ambient temperature for 4 hours. The reaction was concentrated and washed with Et ₂ O, and finally washed with water then Et ₂ O. The pale yellow solid was dried to give 0.027 g of crude material. The crude material was purified by reverse phase chromatography eluting with a gradient from 0 to 90% ACN / water to afford &lt;RTIgt; MS (ES+APCI) m/z = 510 (M+H).

Example 154

N-(1-Benzyl-1H-indazol-4-yl)-6-cyanoimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 152 using 6-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid instead of 7-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid. MS (ES+APCI) m/z = 393 (M+H).

Example 155

N-(1-Benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 1-benzyl-4-nitro-1H-carbazole : 4-nitro-1H-carbazole (1.00 g; 6.13 mmol), benzyl bromide (1.15 g; 6.74 mmol) Potassium carbonate (1.69 g; 12.3 mmol) was combined with DMF (15 mL) and stirred at room temperature under nitrogen for 16 h. The reaction mixture was added to water (50 mL) andEtOAc was evaporated. The combined extracts were dried (Na2SO4) This material was purified by gel chromatography using hexane/ethyl acetate (20:1 to 10:1 to 5:1). The first isolating component was the desired regioisomer (730 mg) obtained as a yellow solid. Another regioisomer is the second dissolving component (650 mg).

Step B: Preparation of 1-benzyl-1H-indazole-4-amine : heating 1-benzyl-4-nitro-1H-carbazole (150 mg; 0.592 mmol), iron powder (331) under reflux A mixture of ammonium chloride (16 mg; 0.296 mmol) in ethanol/water (4:1; 5 mL) for 5 h. The solvent was removed in vacuo and the residue was crystalljjjjjjjjjjjjjjj The mixture was allowed to cool and then filtered through a pad of EtOAc and washed with ethyl acetate. The solvent was removed in vacuo to give the desired material which was used directly in next step.

Step C: Preparation of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate : Stirring 5-bromopyridin-2-amine (5.22 g) in ethanol (151 mL, 30.2 mmol) under nitrogen , a mixture of 30.2 mmol) and ethyl 2-chloro-3-oxopropionate (5.00 g, 33.2 mmol) (Toronto Research Chemicals; 5% benzene solution). The mixture was heated to 75 ° C for 4 hours and then heated at ambient temperature for 2 days. The solvent was removed in vacuo to give a crystal crystals crystals eluted elute 30%).

Step D: Preparation of 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid : lithium hydroxide (0.427 g, 17.8 mmol) was added to the stirred 6-bromoimidazo[1,2-a]pyridine Ethyl 3-carboxylate (2.40 g, 8.92 mmol) in 20 mL of a 4:1 THF/ethanol mixture. The mixture was stirred under nitrogen at ambient temperature for 3 days. The pH of the mixture was adjusted to neutral (by addition of an aqueous mineral acid solution) to induce precipitation of a large amount of off-white solid. The solid was isolated by filtration and dried <RTI ID=0.0>

Step E: Preparation of N-(1-benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide : in catalytic (0.005 mL) amount In the presence of DMF, 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (200 mg; 0.83 mmol) was suspended in dichloromethane (2 mL). A solution of grass chloroform (0.913 mmol; 2 M dichloromethane solution) was added. Stir the mixture in a sealed vial (occasionally vented to release gas) until the bubble is stopped (about 30 minutes). A white suspension was obtained. Diisopropylethylamine (188 μL; 1.08 mmol) was added. A clear solution was obtained. A solution of 1-benzyl-1H-indazole-4-amine (185 mg; 0.83 mmol) in dichloromethane was added followed by diisopropylethylamine (188 uL). The mixture was stirred at ambient temperature for 24 hours. A suspension is obtained. The mixture was diluted with ether (10 mL) and a solid was collected by filtration. The filter pad was washed with diethyl ether and water and dried (EtOAc) MS (APCI) positron emission scan, m/z = 446, 449 (M+H).

Example 156

N-(1-Benzyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-chloro-4-(2-methoxyethoxy)pyridine : The flask was charged with 2-chloro-4-nitropyridine (100 g, 630.7 mmol) under dry nitrogen atmosphere. 2-methoxyethanol (746.8 mL, 9461 mmol). The mixture was cooled to 0 ° C with stirring using an ice/water bath. Potassium 2-methylpropan-2-carboxylate (81.95 g, 693.8 mmol) was added and the mixture was stirred for 30 min. The ice/water bath was removed and the mixture was stirred at ambient temperature for a further 2 hours. The mixture was concentrated in vacuo. Water (500 mL) was added and the mixture was extracted with dichloromethane. The combined extracts were dried with EtOAc EtOAc m.

Step B: Preparation of 4-(2-methoxyethoxy)pyridin-2-amine : 2-chloro-4-(2-methoxyethoxy)pyridine (30.0 g; 159.9 mmol), X-PHOS (3.03 g, 6.356 mmol) and bis(dibenzylideneacetone)dipalladium (2.26 g; 2.468 mmol) were combined in a reaction flask. Anhydrous tetrahydrofuran (150 mL) was added. The flask was degassed by alternately evacuating the flask followed by filling with dry nitrogen (3 times). The mixture was cooled to 0-5 ° C using an ice/water bath. LHMDS (325 mL, 325.0 mmol) was added via an addition funnel while maintaining the temperature below 5 °C. The ice/water bath was removed and the mixture was heated to reflux (60-65 ° C) for 1.5 hours. After allowing the mixture to cool, the ice/water bath was placed in situ. Hydrochloric acid (2 N; 300 mL) was added with stirring to maintain the temperature below 30 °C. After stirring for 15 minutes, the mixture was transferred to a sep. funnel eluted with methyl t-butyl ether (300 mL) and water (20 mL). Separate the phases. The aqueous phase was basified by addition of sodium hydroxide (50%; 10 mL) and then extracted with dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and filtered. Heptane (300 mL) was added. The solution is concentrated in vacuo to about one-third of the original volume. Heptane (200 mL) was added. Further concentration causes a solid to precipitate. The solid was collected by filtration and washed with heptane (100 mL). The solid was dried under vacuum <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI><RTIgt;

Step C: Preparation of ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate : 4-(2-A) in a reaction flask under a dry nitrogen atmosphere Oxyethoxy)pyridine-2-amine (5.00 g; 29.7 mmol) was mixed with ethanol (20 mL). A solution of ethyl 2-chloro-3-oxopropionate (5% benzene solution; 110 mL; solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60 ° C under nitrogen for 4 hours. After the mixture was cooled, the solvent was evaporated in vacuo to give a brown solid (9 g). The solid was mixed with ethyl acetate (200 mL) and sodium hydrogen carbonate solution (50 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted with ethyl acetate (50 mL). The combined ethyl acetate extracts were dried with sodium s This material was dissolved in ethyl acetate and passed through a short ruthenium dioxide column and eluted with ethyl acetate. The product-containing fraction was concentrated to give ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (3.77 g) as a cream solid.

Step D: Preparation of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid : 7-(2-methoxyethoxy)imidazo[1,2 -a]Phenyl-3-carboxylate (6.06 g; 22.9 mmol) was mixed with tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL). Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. The mixture was stirred under a nitrogen atmosphere and heated at 40 ° C for 22 hours. The mixture was allowed to cool and then concentrated under reduced pressure to give a yellow gum. Water (50 mL) was added and the mixture was stirred until homogeneous. Hydrochloric acid (2 N) was added with stirring to adjust to pH 3. The mixture was cooled with an ice/water bath. The resulting precipitate was collected by filtration and washed with a little water (10 mL). The material was dried in vacuo to give 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (4.90 g).

Step E: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamidine Amine : Addition to a suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (50 mg; 0.21 mmol) in dichloromethane (2 mL) A quantity of DMF was catalyzed (0.005 mL) followed by the addition of chloroform (0.23 mmol; 2 M dichloromethane). The mixture was stirred in a sealed vial until bubbling ceased (about 30 minutes) with occasional venting to release the gas. Add a solution of 1-benzyl-1H-indazole-4-amine (Example 155, Step AB; 47 mg; 0.21 mmol) in dichloromethane (1 mL), then diisopropylethylamine (33) Mg; 0.25 mmol). The mixture was stirred at ambient temperature for 16 hours during which time a suspension formed. The mixture was partitioned between water and dichloromethane and the suspension was extracted several times with dichloromethane. The combined organic phases (containing suspended solids) were concentrated under reduced pressure. The resulting solid material was triturated with diethyl ether and collected by filtration. The solid was washed with diethyl ether, water and then diethyl ether. The material was dried <RTI ID=0.0> MS (APCI), m/z = 442.2 (M+H).

Example 157

N-(1-Benzyl-1H-indazol-4-yl)-7-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate : 4-bromopyridin-2-amine (10.0 g, 0.06 mol) in a reaction flask under dry nitrogen atmosphere Mix with ethanol (50 mL). A solution of ethyl 2-chloro-3-oxopropionate (5% benzene solution; 222 mL; solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60 ° C under nitrogen for 5 hours. After allowing the mixture to cool, the solvent was removed in vacuo to afford a brown solid. The solid was mixed with ethyl acetate (500 mL) and sodium hydrogen carbonate solution (200 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were dried with sodium s The crude material was dissolved in EtOAc (EtOAc m.) g).

Step B: Preparation of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid : ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (15 g, 56 mmol) Lithium hydroxide monohydrate (3 g, 71.4 mmol) was added to a solution of tetrahydrofuran/ethanol/water (1:2:1, total 560 mL). After stirring overnight at ambient temperature, the solvent was removed in vacuo to afford a yellow gum. Water (300 mL) and dichloromethane were added and the phases were separated. The aqueous layer was cooled in an ice water bath and then the pH was adjusted to 3 using 2 N sulfuric acid. The product precipitated and was collected by suction and washed with EtOAc (EtOAc)EtOAc.

Step C: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide : to 7 -bromoimidazo [ 1,2-a]pyridine-3-carboxylic acid (42 mg; 0.17 mmol) in dichloromethane (1 mL) was added dichloromethane (1.1 eq; 2 M dichloromethane). DMF. The mixture was stirred in a sealed container and stirred until the bubbling ceased, occasionally venting to release the gas. 1-Benzyl-1H-indazol-4-amine (Example 155, Step AB; 39 mg; 0.17 mmol) was added followed by diisopropylethylamine (2 eq.). The mixture was stirred at ambient temperature for 2 days. The mixture was diluted with MeOH and solid was collected by filtration and washed twice with 2M aqueous sodium carbonate, water and diethyl ether. The solid was then dried to give the desired product (53 mg).

Step D: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-vinylimidazo[1,2-a]pyridine-3-carboxamide : N- under nitrogen (1-Benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide (50 mg; 0.112 mmol), tributylvinyltin A mixture of (43 mg; 0.13 mmol) and cesium fluoride (34 mg; 0.22 mmol) was combined with DMF (1 mL). Palladium(II) chloride (0.8 mg; 0.005 mmol), tri-tert-butylphosphine (18 mg; 0.009 mmol) and copper (I) iodide (1.7 mg; 0.009 mmol) were added and the mixture was purged with nitrogen. It was then heated in a sealed container at 45 ° C for 16 hours. The mixture was added to water (30 mL) and extracted into ethyl acetate. The combined extracts were washed with water, dried (sodium sulfate) and filtered th The solvent was removed in vacuo to give a white solid.

Step E: Preparation of N-(1-benzyl-1H-indazol-4-yl)-7-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamidine Amine : to N-(1-benzyl-1H-indazol-4-yl)-7-vinylimidazo[1,2-a]pyridine-3-carboxamide (27 mg; 0.069 mmol) Add osmium tetroxide (0.1 eq, 2% tributanol solution) and N-methylmorpholine N-oxide (1.2 eq, 50% in water) to a solution of acetone/water (3:2; 1 mL) . The mixture was stirred at ambient temperature for several days. Aliquots of osmium tetroxide and N-methylmorpholine N-oxide were added at intervals until the reaction was completed by LC. The mixture was added to water and extracted into ethyl acetate. Some insoluble matter was separated by filtration. The extracts were combined, concentrated in vacuo and combined with a solid isolated by filtration. The combined material was purified by preparative EtOAc EtOAc (EtOAc:EtOAc) MS (APCI), m/z = 428.2 (M+H).

Example 158

N-(1-Benzyl-1H-indazol-4-yl)-6-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of N-(1-benzyl-1H-indazol-4-yl)-6-vinylimidazo[1,2-a]pyridine-3-carboxamide : under nitrogen, at 60 N-(1-Benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide was stirred at ° C (Example 155; 75 mg; 0.168 mmol) ), tributyl(vinyl)stannane (59 mg; 0.185 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (2.3 mg; 0.0025 mmol), bis(tri-tert-butylphosphine) A mixture of palladium (0) (2.6 mg; 0.0050 mmol) and cesium fluoride (56 mg; 0.37 mmol) in NMP for 5 h. A certain amount of palladium catalyst and tributyl(vinyl)tin (amount similar to the initial addition amount) were further added, and the mixture was further heated for 12 hours. The mixture was added to water (20 mL) and extracted into ethyl acetate. The combined extracts were washed with water and brine and dried (sodium sulfate). The filtered solution was concentrated under reduced pressure. This material was purified by silica gel chromatography eluting with ethyl acetate to give the desired product (yield: 66 mg) as an oil.

Step B: Preparation of N-(1-benzyl-1H-indazol-4-yl)-6-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamidine Amine : Stirring N-(1-benzyl-1H-indazol-4-yl)-6-vinylimidazo[1,2-a]pyridine-3-carboxamide at ambient temperature (63 mg; 0.16 mmol), osmium tetroxide (0.008 mmol; 2.5% solution of t-butanol) and N-methylmorpholine N-oxide (21 mg; 0.18 mmol) in acetone/water (3:2; 1 mL) The mixture was allowed to stand for 24 hours. Further osmium tetroxide (250 L of a 2.5% solution in the third butanol) was added and the mixture was stirred for a further 24 hours. The mixture was diluted with ethyl acetate and the solid was separated by filtration. The material was purified by EtOAc (EtOAc/EtOAc) MS (APCI), m/z = 428.2 (M+H).

Example 159

N-(1-Benzyl-1H-indazol-4-yl)-6-methoxyimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid: substituting 5-methoxypyridin-2-amine for 2-aminoisonephrine according to the procedure of Example 152, Step AB Nitrile is prepared.

Step B: Preparation of 1-benzyl-4-nitro-1H-carbazole: 4-nitro-1H-carbazole (0.500 g, 3.06 mmol) in acetone (0.4 M, 7.5 mL). KOH (0.258 g, 4.60 mmol) was added to the solution. After 15 minutes at 0 ° C, (bromomethyl)benzene (0.400 mL, 3.37 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated with EtOAc EtOAcjjjjjjjj

Step C: Preparation of 1-benzyl-1H-indazole-4-amine : 1-Benzyl-4-nitro-1H-indazole (672 mg, 2.65 mmol) was dissolved in 26 mL EtOH / water ( 4:1) was treated with NH4Cl (0.5 eq.) and Fe powder (10 eq.). The reaction was heated to reflux for 2 hours. The reaction was concentrated under reduced pressure, using _{EtOAc: Et 3 N (4:} 1) was diluted and stirred for 2 hours. The reaction mixture was filtered through GF/F filter paper and concentrated to afford a brown oil. The crude material was purified by EtOAcqqqqqq

Step D: Preparation of N-(1-benzyl-1H-indazol-4-yl)-6-methoxyimidazo[1,2-a]pyridine-3-carboxamide : 6-methoxy Imidazo[1,2-a]pyridine-3-carboxylic acid (29.5 mg, 0.154 mmol) was dissolved in DCM. Grass grass chlorine (1.1 equivalents) was added followed by 1 drop of DMF. The reaction was stirred at ambient temperature until foaming ceased, and then 1-benzyl-1H-indazole-4-amine (34.3 mg, 0.154 mmol) was then added, followed by DIEA (1.2 eq.). The reaction was stirred at ambient temperature overnight. The reaction was concentrated, purified with EtOAc EtOAc (EtOAc) MS (ES+APCI) m/z = 398.3 (M+H).

Example 160

Preparation of N3-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3,6-dimethylguanamine

Prepared according to the procedure of Example 159 using 6-amine-carbamimidazo[1,2-a]pyridine-3-carboxylic acid instead of 6-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid. MS (ES+APCI) m/z = 411.3 (M+H).

Example 161

N-(1-Benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the procedure of Example 159 using 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid instead of 6-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid.

Claims (33)

a compound of formula I or a pharmaceutically acceptable salt thereof, Wherein: R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ -, hetAr ³ CH ₂ -, (3-6C cycloalkyl)-CH ₂ -, hetCyc ¹ CH ₂ -, Ar ¹ (CH ₂ ) _n - or (N-1-3C alkyl)pyridinyl-CH ₂ -; hetAr ¹ is a 6-membered heteroaryl group having 1-2 ring N atoms, which is unsubstituted or one or more Substituent independently selected from (1-6C)alkyl, (1-4C)alkoxy, halogen, CF ₃ or (3-6C)cycloalkyl; m is 0, 1 or 2; hetAr ² is a 5-membered heteroaryl ring independently selected from the group consisting of ring heteroatoms of N and S, wherein at least one of the heteroatoms is N, wherein the ring is unsubstituted or independently selected from one or more 6C) a substituent of an alkyl group; hetAr ³ is a 1H-benzo[d]imidazol-5-yl group; hetCyc ¹ is a 6-membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, It is unsubstituted or substituted by -C(=O)(1-6C alkyl) or -C(=O)O(1-6C alkyl); Ar ¹ is unsubstituted or independently selected by one or more From halogen, (1-6C)alkyl, CN, CF ₃ , OH, (1-6C) alkoxy, -C(=O)OH, -C(=O)O(1-6C alkyl), ^{-C (= O) NR a R} b , or benzyloxy substituent of the substituted phenyl group; R ^a and R ^b are independently H or (1-6C) alkyl; n is 0 1 or ^2; R 2 is H, F, Cl or CH ^_3; R ₃ is H, F or Cl; R ⁴ is H, CN, F, Cl, Br, -OMe, -OCF 3, -CF 3, - CH(OH)CH ₂ OH or -C(=O)NH ₂ ; R ^{5 is} selected from the group consisting of: H, halogen, CN, OH, hetAr ⁴ , hetAr ⁵ , hetCyc ² , hetCyc ³ (1-4C alkyl)-, hetCyc ⁴ (1-4C) alkoxy, hetCyc ⁵ (1-4C) alkoxy, (1-3C alkoxy) (1-4C) alkoxy, hydroxy (1-6C) alkoxy, two Hydroxy (2-6C) alkoxy, (1-6C) alkoxy, [hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy) (1-4C alkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4C alkyl)C(=O) -, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [bis(1-3C alkyl)amino](1-4C)alkoxy, N-(1-3C alkyl) Pyridone; hetAr ⁴ is a 5-membered heteroaryl ring having 2 ring N atoms, wherein the ring is unsubstituted or substituted with one or more alkyl substituents independently selected from (1-6C); hetAr ⁵ is Pyridyl group, which is unsubstituted or substituted with one or more substituents independently selected from (1-6C)alkyl; hetCyc ² is a 5-6 member saturated or partially unsaturated heterocyclic having 1-2 ring N atoms Ring; hetCyc ³ has 1-2 independent choices a 5-6 membered heterocyclic ring from a hetero atom of N and O, wherein hetCyc ^{3 is} unsubstituted or substituted with one or more substituents independently selected from (1-6C)alkyl; hetCyc ⁴ is 1-2 5-6 membered heterocyclic rings independently selected from the ring heteroatoms of N and O, wherein the ring is unsubstituted or independently selected from (1-6C)alkyl, (1-4C alkoxy) by one or more a substituent of (1-6C)alkyl and (1-4C)alkyl-OC(=O)-; hetCyc ⁵ is a spiroheterocycle having two ring heteroatoms independently selected from N and O, wherein hetCyc ^{5 is} unsubstituted or substituted with a group selected from a (1-6C) alkyl group; and R ⁶ is H or Cl. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ -. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ¹ is hetAr ¹ (CH ₂ ) _m -. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein m is 1. A compound of the formula I or a pharmaceutically acceptable salt thereof, wherein R ¹ is (3-6C cycloalkyl)-CH ₂ -, hetCyc ¹ CH ₂ -, Ar ¹ (CH ₂ ) _n - or (N-1-3C alkyl)pyridinyl-CH ₂ -. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁵ is selected from the group consisting of H, halogen, CN and OH. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁵ is hetAr ⁴ or hetAr ⁵ . A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁵ is hetCyc ² or hetCyc ³ (1-4C alkyl)-. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁵ is hetCyc ⁴ (1-4C) alkoxy or hetCyc ⁵ (1-4C) alkane Oxygen. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to claim ⁹ , wherein R ⁵ is hetCyc ⁴ (1-4C) alkoxy. The compound of the formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁵ is selected from (1-3C alkoxy)(1-4C)alkoxy, Hydroxy (1-6C) alkoxy, dihydroxy (2-6C) alkoxy, (1-6C) alkoxy, [hydroxy(2-4C)alkyl)amino]-(1-4C) alkane , [(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, ( 1-4C alkyl)C(=O)-, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl and [di(1-3C alkyl)amino](1-4C)alkane Oxygen. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁵ is selected from N-(1-3C alkyl)pyridone. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ² is H. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ² is F or Cl. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ² is CH ₃ . A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ³ is H. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ³ is F or Cl. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁴ is H. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁴ is CN, Br, -OMe, -CH(OH)CH ₂ OH or -C ( =O) NH ₂ . A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁶ is H. A compound of formula I , or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R ⁶ is Cl. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to claim 1, wherein: R ¹ is hetAr ¹ (CH ₂ ) _m -, hetAr ² CH ₂ - or hetAr ³ CH ₂ -; hetAr ¹ is a 6-membered heteroaryl having 1-2 ring N atoms which is unsubstituted or independently selected from (1-6C)alkyl, (1-4C)alkoxy, halogen, CF ₃ or (3-6C) a substituent of a cycloalkyl group; m is 0, 1 or 2; hetAr ² is a 5-membered heteroaryl ring having 2 ring heteroatoms independently selected from N and S, wherein the heteroatoms At least one of them is N, wherein the ring is unsubstituted or substituted with one or more substituents independently selected from (1-6C)alkyl; hetAr ³ is 1H-benzo[d]imidazol-5-yl; R ² is CH ₃ ; R ³ is H; R ⁴ is H; R ⁵ is hetCyc ⁴ (1-4C) alkoxy or hetCyc ⁵ (1-4C) alkoxy; hetCyc ⁴ is 1-2 independent a 5-6 membered heterocyclic ring selected from the group consisting of ring heteroatoms of N and O, wherein the ring is unsubstituted or independently selected from (1-6C)alkyl, (1-4C alkoxy) by one or more -6C) substituted with a substituent of alkyl and (1-4C)alkyl-OC(=O)-; hetCyc ⁵ is a spiroheterocycle having 2 ring heteroatoms independently selected from N and O, wherein hetCyc ^{5 is} not Substituted or selected 1-6C) a group substituted with an alkyl group; and R ⁶ is H. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to claim 22, wherein: R ¹ is hetAr ¹ (CH ₂ ) _m -; hetAr ¹ is a 6-membered heterocyclic ring having 1-2 ring N atoms. An aryl group which is unsubstituted or substituted with one or more substituents independently selected from (1-6C)alkyl, (1-4C)alkoxy, halogen, CF ₃ or (3-6C)cycloalkyl m is 1; R ⁵ is hetCyc ⁴ (1-4C) alkoxy; and hetCyc ⁴ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein the ring is not Substituted or substituted by one or more independently selected from (1-6C)alkyl, (1-4C alkoxy)(1-6C)alkyl and (1-4C)alkyl-OC(=O)- Substituent substitution. A compound of the formula I , or a pharmaceutically acceptable salt thereof, according to claim 23, which is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. A compound selected from the group consisting of N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazole-4- -7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-(4-ethylpiperazine-1) -yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2 -a]pyridine-3-carbamide; 7-(2-(2,6-diazaspiro[3.3]hept-2-yl)ethoxy)-N-(1-((6-isopropyl) Pyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride; N-(1 -((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2,6-diaza Heterospiro[3.3]hept-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-(2-oxa-6-azaspiro[3.3] ]hept-6-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazolium [1,2-a]pyridine-3-carboxamide; 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropyl) Pyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((6-) Isopropyl pyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((3S,5R)-3,4,5-trimethylperidazole) Pyrazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((1-isopropyl-5-)- -1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2,6-diazaspiro[ 3.3]hept-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((1-isopropyl-5-methyl-1H-py) Zyrid-3-yl)methyl)-3-methyl- 1H-carbazol-4-yl)-7-(2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a Pyridine-3-carboxamide; N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazole- 4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-( (1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methyl) -1,4-diazepan-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((2-isopropylthiazole) 4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1, 2-a]pyridine-3-carboxamide; N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7 -(2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 7- (2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl)- 3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-(4-isopropylpiperazin-1-yl) Oxy)-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a Pyridine-3-carboxamide; N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2 -(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((6-cyclopropylpyridine-2) -yl)methyl)-3-methyl-1H-carbazole-4- -7-(2-(4-ethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((6-) Cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(N-morpholinyl)ethoxy)imidazo[1,2 -a]pyridine-3-carbamide; N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7- (2-(3,3,4-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((6-) Cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-(2-methoxyethyl)piperazine-1- Ethyl)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H -oxazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N- (1-((6-Cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1- Ethyl)imidazo[1,2-a]pyridine-3-carboxamide; (S)-N-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl) -1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3- Methionine; (S)-N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2 -(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; (S)-7-(2-(3,4 -Dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-iso) Propylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; (S)-N-( 1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazine- 1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride; (R)-N-(1-((6-cyclopropylpyridin-2-yl) )methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2 -a]pyridine-3-carbamide dihydrochloride; (R)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-( (6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; (S) -7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((1-isopropyl-5-methyl-1H-pyrazole-3) -yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; (S)-7-(2-(3, 4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazole-4 -yl)imidazo[1,2-a]pyridine-3-carboxamide; (S)-N-(1-((6-t-butylpyridin-2-yl)methyl)-3-methyl -1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridyl 3-carbamamine; (S)-N-(1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7- (2-(3,4-Dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; (S)-N-(1-(( 6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-carbazole 4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; (S) -7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(1-((4,6-dimethylpyridin-2-yl)methyl)- 3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; (S)-7-(2-(3,4-dimethylpiperazine) -1-yl)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide; (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6- Ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-(( 6-Secontapyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((S)-3,4-dimethylpiperazine) -1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; (S)-7-(2-(3,4-dimethylpiperazin-1-yl) Ethoxy)-N-(3-methyl-1-((5-propylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-carbamamine; (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-isopropylpyridine)- 2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; (S)-7-(2-(3) 4-Dimethylpiperazine -1-yl)ethoxy)-N-(1-((6-isobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1 , 2-a]pyridine-3-carboxamide; (S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5) -fluorine- 6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; (S)- 7-(2-(3,4-Dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-(2-(6-methylpyridin-2-yl)) (1)-oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; (S)-N-(1-((6-cyclopropylpyridin-2-yl) )methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazolium [1,2-a]pyridine-3-carboxamide; 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-(( 5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-( 4-isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indole (Z)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3 -methyl-1H-indazol-4-yl)-7-(2-(3-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidine Amine; N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperidin Pyrazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((1-isopropyl-1H-pyrazole)- 3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2 -a]pyridine-3-carboxamide dihydrochloride; N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indole Zin-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(3 -methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(6-methylpyridin-3-yl)imidazo[1, 2-a]pyridine-3-carboxamide dihydrochloride; N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl - 7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride; N-(3-methyl-1) -((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperidin-4-yl)imidazo[1,2-a]pyridine-3- Formamide trihydrochloride; 7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[ 1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)- 7-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride; N-(3-methyl-1-((6-methylpyridine-2) -yl)methyl)-1H-indazol-4-yl)-7-(2-(pyrrolidin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide Dihydrochloride; 4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylaminemethyl) Imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-methyl Third butyl ester; 7-(2-hydroxyethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl Imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride Salt; 7-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl Imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazole-4 -yl)-7-(2-(N-morpholinyl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-(dimethylamino)ethyl Oxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine- 3-carbalamine; N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a] Pyridyl-3-carboxamide; 6-cyano-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazolium [1,2-a]pyridine-3-carboxamide; 7-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-carbazole- 4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indole Zin-4-yl)-7-(2-(piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1 -((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-6-oxooxy-1,6-dihydropyridine-3 -yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((6-isopropylpyridine)- 2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2 -a]pyridine-3-carbamide; N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2 -(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methyl) Pyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3- Methionamine; 7-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl) -1H-oxazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridin-2-yl)) -1H-indazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl- 1-((6-Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazol-5-yl)imidazo[1, 2-a]pyridine-3-carboxamide; 7-(2-(dimethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)) Methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-hydroxyethyl)-N-(3-methyl-1- ((6-Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-(2- Methoxyethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide; 7-(1-(2-hydroxyethylamino)ethyl)-N-(3-methyl-1-(6-A) Pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(1-Hydroxyethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7- (2-(pyrrolidin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridine-2) -yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3- Methionamine; 7-acetamido-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1, 2-a]pyridine-3-carboxamide; N-(1-benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazolium [1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-methoxyethoxy)-N-(3-methyl-1-((tetrahydro-2H-pyran)- 2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-methoxyethoxy)-N-( 3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide ;N-(1-(cyclopropylmethyl)-3-methyl-1H-indazol-4-yl)-7-(2-methoxy Ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indole Zin-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1- ((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazole-4- -7-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((6-) Methoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazole And [1,2-a]pyridine-3-carboxamide; N-(3-methyl-1-((2-methylthiazol-4-yl)methyl)-1H-indazol-4-yl - 7-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(3-methyl-1- ((6-Methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[ 1,2-a]pyridine-3-carboxamide tetrahydrochloride; N-(1-benzyl-1H-indazol-4-yl)-7-(2-(N-morpholinyl) Oxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)-7-(2,3-dihydroxypropoxy Imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)-7-hydroxyimidazo[1,2-a] Pyridine-3-carbamide; 3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-carbazole Methyl-1-methyl)methyl)benzoate; N-(1-(3-aminomethylbenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy Imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-A Ethyloxy)-N-(1-(3-(methylaminomethyl)benzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-methyl Indoleamine; 3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a] Pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoic acid methyl ester dihydrochloride; N-(1-(3-(dimethylaminecarbamimidyl)benzene) -1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide Dihydrochloride; 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(3-(trifluoromethyl)benzyl)-1H-carbazole 4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride; N-(1-(3-cyanobenzyl)-1H-indazol-4-yl) -7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(5-chloro-1-(3) -(trifluoromethyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2- a]pyridine-3-carboxamide; N-(7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2- (4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride; 7-(2-(4-methylpiperazine- 1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide III Hydrochloride; 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl) -1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3- Formamide trihydrochloride; N-(1-((1-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl - 7-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride; N-(1-((6-ethoxypyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)B Oxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-indazole-4 -yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride; 7-(2 -(4-methylpiperazin-1-yl)ethoxy)-N-(1-(2-(pyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1 , 2-a]pyridine-3-carboxamide; N-(1-((1H-benzo[d]imidazol-5-yl)methyl)-1H-indazol-4-yl)-7-( 2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride; N-(1-(2,4-di) Fluorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1- (cyclopropylmethyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 7-( 2-methoxyethoxy)-N-(1-(pyridin-4-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide 7-(2-methoxyethoxy)-N-(1-(pyridin-2-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3 -carbamamine; 7-(2-methoxyethoxy)-N-(1-((tetrahydro-2H-pyran)- 4-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-(4-methoxybenzyl)- 1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-(cyclohexylmethyl) -1H-carbazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl) Piperidine-1-carboxylic acid tert-butyl ester; (R)-3-((4-(7-(2-methoxyethoxy))imidazo[1,2-a]pyridine-3-carboxamide -1H-indazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester; 7-(2-methoxyethoxy)-N-(1-((2-methyl) Pyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-(3-(benzyloxy) Benzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2- Methoxyethoxy)-N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-methyl Indoleamine; 7-(2-methoxyethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine 3-carbamamine; 4-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazole- 1-butyl)methyl)piperidine-1-carboxylic acid tert-butyl ester; 2-((4-(7-(2-methoxyethoxy))imidazo[1,2-a]pyridine-3- Methionamine)-1H-indazol-1-yl)methyl)morpholine-4-carboxylic acid tert-butyl ester; 7-(2-methoxyethoxy)-N-(1-((6) -methylpyridin-3-yl)methyl)- 1H-carbazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)-7-methoxy Imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidine Amine; N-(1-benzyl-1H-indazol-4-yl)-7-ethoxyimidazo[1,2-a]pyridine-3-carboxamide; N-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N -(1-(pyridin-2-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-(3-hydroxybenzene) Methyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-methoxy Ethyloxy)-N-(1-(piperidin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride N-(1-((1-Ethylpiperidin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1] , 2-a]pyridine-3-carboxamide; 7-(2-methoxyethoxy)-N-(1-phenyl-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide; N-(1-benzyl-5-bromo-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1, 2-a]pyridine-3-carboxamide; N-(1-benzyl-7-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[ 1,2-a]pyridine-3-carboxamide; N-(1-benzyl-5,7-dichloro-1H-indazol-4-yl)-7-(2-methoxyethoxy Imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-5-chloro-1H-indazol-4-yl)-7-(2-methoxy Ethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-( (6-isopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[ 1,2-a]pyridine-3-carboxamide; N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-1H-indazole- 4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridin Acridine-3-carboxamide; N-(1-(3-methoxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1 , 2-a]pyridine-3-carboxamide; N-(1-(3-chlorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazole And [1,2-a]pyridine-3-carboxamide; 7-(2-methoxyethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)- 1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-methoxyethoxy)-N-(1-(3-methylbenzene) Methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)-6 -fluoroimidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)-7-(1H-pyrazol-4-yl) Imidazo[1,2-a]pyridine-3-carboxamide; 7-ethenyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a] Pyridine-3-carboamine; N-(1-benzyl-1H-indazol-4-yl)-7-(1-hydroxyethyl)imidazo[1,2-a]pyridine-3-methyl Indoleamine; N-(1-benzyl-1H-indazol-4-yl)-7-(1-(N-morpholinyl)ethyl)imidazo[1,2-a]pyridine-3- Methionamine; 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((2-methylthiazol-5-yl)methyl)-1H-indole Zin-4-yl)imidazo[1,2-a]pyridine-3-carboxamide; 7-(2-(4- Piperazin-1-yl)ethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2- a]pyridine-3-carbamide; 7-(2-methoxyethoxy)-N-(1-phenethyl-1H-carbazol-4-yl) Zyrazolo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)-7-cyanoimidazo[1,2-a]pyridine 3-carbamamine; N-(1-benzyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[ 1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-indazol-4-yl)-6-cyanoimidazo[1,2-a]pyridine-3- Methionamine; N-(1-benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzamide -1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl- 1H-indazol-4-yl)-7-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H- Oxazol-4-yl)-6-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide; N-(1-benzyl-1H-carbazole 4-yl)-6-methoxyimidazo[1,2-a]pyridine-3-carboxamide; N3-(1-benzyl-1H-indazol-4-yl)imidazo[1 , 2-a]pyridine-3,6-dimethylamine; and N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine- 3-carbamide; and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a compound of claim 25, or a pharmaceutically acceptable salt thereof, and a medicinal An acceptable diluent or carrier. A use of a compound of formula I according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a compound of claim 25, or a pharmaceutically acceptable salt thereof, for use in the preparation of A medicament for treating a disease or condition selected from the group consisting of a bone related disease, a cancer, an autoimmune disease, an inflammatory disease, a cardiovascular disease, a fibrosis, a pain, and a burn. The use of claim 27, wherein the disease or condition is fibrosis. The use of claim 27, wherein the disease is cancer. The use of claim 29, wherein the cancer is multiple myeloma, acute myeloid leukemia, chronic myelogenous leukemia, prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, giant cell tumor of bone , giant cell tumor of tendon sheath, tumor metastasis to other tissues, myelofibrosis, pigmented villonodular synovitis or gastrointestinal stromal tumor. The use of claim 30, wherein the cancer is acute myeloid leukemia. The use of claim 30, wherein the cancer is gastrointestinal stromal tumor. A method for the preparation of a compound of claim 1, which comprises: (a) bringing a corresponding compound of formula II Wherein Z ¹ is COOH or a reactive derivative thereof; and the corresponding compound of formula III Coupling in the presence of a coupling reagent; or (b) bringing a corresponding compound of formula IV Compound with formula III Coupling in the presence of a base; or (c) a compound of formula I wherein R ⁵ is hetCyc ⁴ (1-4C)alkoxy, (hetCyc ⁷ )-O- or hydroxy(1-6C)alkoxy, such that V compound Wherein X ¹ is F or Cl; and reacting with a compound having the formula hetCyc ⁴ (1-4C)alkyl-OH, hetCyc ⁷ -OH or P ¹ O-(1-6C)alkyl-OH in the presence of a base, wherein P ¹ is a hydroxy protecting group; or (d) for R ⁵ is hetCyc ^2, wherein hetCyc ² nitrogen group of a compound of formula I, the corresponding compound of formula Va Reacting with a compound having the formula hetCyc ² -H; or (e) for a compound of formula I wherein R ⁵ is hetAr ⁴ wherein hetAr ⁴ is a nitrogen group, the corresponding compound of formula Va is obtained Reacting with a compound having the formula hetAr ⁴ -H in the presence of a base; or (f) formula I for a carbon linking substituent selected from the group consisting of hetAr ⁴ , hetAr ⁵ and N-(1-3C alkyl)pyridone for R ⁵ a compound that gives the corresponding compound of formula Vb And compounds having formula VI Wherein ring E is a carbon linkage selected from the group consisting of hetAr ⁴ , hetAr ⁵ and N-(1-3C alkyl) pyridone; respectively; reacted in the presence of a palladium catalyst and a base; or (g) is hetAr for R ^{5 4} or hetAr ⁶ , wherein hetAr ⁴ and hetAr ⁶ are carbon-based compounds of formula I , such that the corresponding compound of formula Vb Reacting with a compound having the formula hetAr ⁴ -H or hetAr ⁶ -H, respectively, in the presence of a palladium catalyst and a base and in the absence of a ligand or in the presence of a ligand; or (m) is a hetCyc ³ (1) for R ⁵ 2C alkyl)-, wherein hetCyc ³ is a nitrogen group, [(1-4C alkoxy)(1-4C alkyl)]amino (1-2C) alkyl or [hydroxy (2-4C) alkyl) a compound of formula I of the amino-(1-2C)alkyl group, corresponding compound of formula XII Wherein n is 0 or 1 and Z is H or Me; respectively with hetCyc ³ -H, [(1-4C alkoxy)(1-4C alkyl)]NH ₂ or [hydroxy(2-4C)alkyl) NH ₂ is reacted in the presence of a reducing agent; or (n) is a pyrazolyl group in which R ¹ is hetAr ² CH ₂ - and hetAr ² is a ring N atom substituted with a substituent selected from or (1- 6C)alkyl- a ring of a compound of formula I such that the corresponding compound of formula XIII Reacting separately with a compound of formula (1-6C)alkyl-X ² in the presence of a base wherein X ² is a leaving group or atom; or (o) is N-(1-3C alkyl for R ¹ a pyridone-CH ₂ -compound of formula I to give the corresponding compound of formula XIV Coupling with (1-3C alkyl)-L ¹ in the presence of a base, wherein L ¹ is a leaving group or atom; or (p) is a hetCyc ³ CH ₂ - for R ⁵ , wherein hetCyc ³ is a nitrogen group a compound of formula I having the corresponding compound of formula XV Wherein L ² is a leaving group; coupling with a compound having the formula hetCyc ³ -H in the presence of a base; or (q) is a hetCyc ⁴ (1-4C) alkoxy group for R ⁵ and an N-methyl group of hetCyc ⁴ a compound of formula I of piperazine-1-oxide to give the corresponding compound of formula XVI Wherein n is 2 or 3; reaction with an oxidizing agent; or (r) for R ⁵ is hetCyc ³ (1-4C alkyl) -, wherein the nitrogen-based compound hetCyc2 ³ of formula I, so that it has the formula XVII Corresponding compound Wherein n is 0, 1, 2 or 3 and L ³ is a leaving group; reacting with a corresponding compound having the formula hetCyc ³ in the presence of a base; or (t) is a CH ₃ C(=O)- for R ⁵ a compound of formula I which gives the corresponding compound of formula Vb And a compound having the formula Coupling in the presence of a palladium catalyst and a ligand followed by treatment with an acid; or (u) for a compound of formula I wherein R ⁵ is HO(CH ₂ CH ₂ )-, treating the corresponding compound of formula XVIII with a reducing agent And if necessary, remove any protecting groups and, if necessary, form their salts.